Propylcarbamate derivatives as inhibitors of serine and cysteine proteases

ABSTRACT

The present invention includes ketone derivatives (I) and (II), which are useful as cathepsin K inhibitors. The described invention also includes methods of making such ketone derivatives as well as methods of using the same in the treatment of disorders, including osteoporosis.

FIELD OF THE INVENTION

The present invention relates to ketone derivatives, compositions andmedicaments containing the same, as well as processes for thepreparation and use of such compounds, compositions and medicaments.Such ketone derivatives are inhibitors of serine and cysteine proteases.Particularly, such ketone derivatives are inhibitors of cysteineproteases of the papain superfamily. More particularly, the ketones ofthe present invention are inhibitors of cathepsin family cysteineproteases such as cathepsin K. Such ketone derivatives are useful in thetreatment of diseases associated with serine and cysteine proteaseactivity, more particularly, in the treatment of diseases associatedwith cathepsin family cysteine proteases, for instance in the treatmentof diseases associated with cathepsin K activity.

BACKGROUND OF THE INVENTION

Osteoclasts are multinuclear cells of hematopoietic lineage, whichfunction in the process of bone resorption. Typically, bone resorptionproceeds through osteoclast adherence to a bone surface and formation ofa tight sealing zone. This activity is followed by extensive membraneruffling on the surface of the osteoclasts. Such action creates anenclosed extracellular compartment on the bone surface that is acidifiedby proton pumps in the ruffled membrane and into which the osteoclastsecretes proteolytic enzymes. The low pH of the compartment dissolveshydroxyapatite crystals at the bone surface, while the proteolyticenzymes digest the protein matrix. In this way a resorption pit isformed. At the completion of this cycle osteoblasts remodel the bone;that is, they deposit a new protein matrix that is subsequentlymineralized at this zone.

Normally, a balance exists between the processes of bone resorption andnew bone formation during remodeling. This normal balance of boneresorption and bone formation, however, may be disrupted resulting in anet loss of bone in each cycle of remodeling. Osteoporosis is areduction in the quantity of bone or atrophy of skeletal tissue.Osteoporosis is characterized by reduced bone mass and disruptions inthe microarchitecture of the bone. These characteristics may lead tofractures, which can result from a minimal amount of trauma. Typicalsites of fractures include vertebral bodies, distal radius, and theproximal femur. However, because those suffering from osteoporosis havegeneral skeletal weakness, fractures may occur at other sites.

Since osteoporosis is characterized by an increase in bone resorptionwith respect to bone remodeling, therapeutic agents that suppress boneresorption should provide a suitable treatment for osteoporosis.Administration of estrogens or calcitonin has been the bone resorptionsuppression treatment typically employed. However, these treatments donot always achieve the desired effect. Consequently, there is acontinuing need for therapeutic agents which can attentuate boneresorption in a subject in need of such attenuation.

Cathepsin K, which has also been called cathepsin O, cathepsin O2, andcathepsin X, is a member of the cysteine cathepsin family of enzymes,which are part of the papain superfamily of cysteine proteases. Otherdistinct cysteine protease cathepsins, designated cathepsin B, cathepsinC, cathepsin F, cathepsin H, cathepsin L, cathepsin S, cathepsin V (alsocalled L2), cathepsin W, & cathepsin Z (also called cathepsin X), havealso been described in the literature. Cathepsin K polypeptide and thecDNA encoding such polypeptide are discussed in U.S. Pat. No. 5,501,969.A crystal structure for cathepsin K is disclosed in PCT PatentApplication WO 97/16177, published May 9, 1997. Cathepsin K isabundantly expressed in osteoclasts under normal conditions and may bethe major cysteine protease present in these cells. See, Tezuka, et al.,J. Biol. Chem., 1994, 269, 1106; Inaoka, et al, Biochem. Biophys. Res.Commun., 1995, 206, 89; and Shi, et al., FEBS Lett., 1995, 357,129. Thisabundant selective expression of cathepsin K in osteoclasts suggeststhat this enzyme is essential for bone resorption. Thus, selectiveinhibition of cathepsin K may provide an effective treatment fordiseases of excessive bone loss, such as osteoporosis.

The selective inhibition of cathepsin K may also be useful in treatingother diseases and conditions. Such disorders include autoimmunediseases such as rheumatoid arthritis, osteoarthritis, neoplasticdiseases, parasitic diseases, and atherosclerosis. For instance,cathepsin K is expressed in the synovium and synovial bone destructionsites of patients with rheumatoid arthritis. See Votta, B. J. et al.; J.Bone Miner. Res. 1997, 12, 1396; Hummel, K. M. et al., J. Rheumatol.1998, 25, 1887; Nakagawa, T. Y. et al., Immunity 1999, 10, 207; Otsuka,T. et al., J. Antibiot. 1999, 52, 542; Li, Z. et al, Biochemistry 2000,39, 529; Diaz, A. et al., Mol. Med. 2000, 6, 648; Moran, M. T. et al.,Blood 2000, 96, 1969.

Cathepsin K levels are elevated in chondroclasts of osteoarthriticsynovium See Dodds, R. A. et al., Arthritis Rheum. 1999, 42, 1588; Lang,A. et al., J. Rheumatol 2000, 27, 1970).

Neoplastic cells also have been shown to express cathepsin K. See,Littlewood-Evans, A. J. et al., Cancer Res. 1997, 57, 5386; Komarova, E.A., et al., Oncogene 1998, 17, 1089; Santamaria, I., et al., Cancer Res.1998, 58, 1624; Blagosklonny, M. V. et al., Oncogene 1999, 18, 6460;Kirschke, H. et al., Eur. J. Cancer 2000, 36, 787; Zhu, D.-M. et al.,Clin. Cancer Res. 2000, 6, 2064.

Cysteine protease inhibitors have been suggested as chemotherapy forparasitic diseases. See, McKerrow, J. H. Int. J. Parasitol 1999, 29,833; Selzer, P. M. et al., Proc. Natl. Acad. Sci 1999, 96, 11015;Caffrey, C. R. et al., Curr. Drug Targets 2000, 1, 155; Du, X. et al.,Chem. Biol. 2000, 7, 733; Hanspal, M. Biochim. Biophys. Acta 2000, 1493,242; Werbovetz, K. A. Curr. Med. Chem 2000, 7, 835.

Elastolytic cathepsins S and K are shown to be expressed in humanatheroma. See, Sukhova, G. K. et al., J. Clin. Invest 1998, 102,576-583; Parks, W. C. J. Clin. Invest 1999, 104, 1167; Shi, G.-P. etal., J. Clin. Invest 1999, 104, 1191; Cao, H. et al., J. Hum. Genet2000, 45, 94.

The present inventors have now discovered novel ketone derivativecompounds, which are inhibitors of serine and cysteine proteaseactivities, more particularly, cathepsin family cysteine proteaseactivities, and most particularly, cathepsin K activity. Such ketonederivatives are useful in the treatment of disorders associated withserine and cysteine protease activity, including osteoporosis, Paget'sdisease, hypercalcemia of malignancy, metabolic bone disease,osteoarthritis, rheumatoid arthritis, periodontitis, gingivitis,atherosclerosis, and neoplastic diseases associated with cathepsin Kactivity.

BRIEF SUMMARY OF THE INVENTION

In a first aspect, the present invention includes compounds of Formula(I):

or a salt, solvate, or pharmaceutically functional derivative thereof,wherein

-   A is the group defined by (Q³)_(p)-(Q²)_(n)-(Q¹)-(Q)_(m)-, wherein    -   Q is CH₂ and m is 0, 1, or 2, or    -   Q is OCH₂ and m is 0 or 1, or    -   Q is N(R³)CH₂ and m is 0 or 1, where R³ is hydrogen or C₁-C₆        alkyl;    -   Q¹ is aryl, heteroaryl, or heterocyclyl;    -   Q² is CH₂ and n is 0 or 1, or    -   Q² is O and n is 0 or 1, or    -   Q² is N(R³) and n is 0 or 1, where R³ is hydrogen or C₁-C₆        alkyl;    -   Q³ is aryl or heteroaryl and p is 0 or 1;-   R¹ is alkyl or cycloalkyl, said cycloalkyl may be optionally    substituted with alkyl;-   D is O or S;-   R² is hydrogen or alkyl; and-   Z is —(X¹)_(q)—(X²);    -   wherein X¹ is S(O)₂, C(O), or —CH₂—, and q is 0, 1, or 2; and    -   X² is aryl, heteroaryl, or heterocyclyl.

In a second aspect, the present invention includes compounds of Formula(II):

or a salt, solvate, or pharmaceutically functional derivative thereof,wherein

-   -   B is -(Q¹)_(a)-(Q² )_(b)-(Q³),        -   wherein,        -   Q¹ is C(O), S(O)₂, or CR²R³, where R² and R³ each are            independently selected from hydrogen or C₁-C₆ alkyl, and a            is 0, 1, 2, or 3;        -   Q² is O, S, NR², or CR²R³, where R² and R³ each are            independently selected from hydrogen or C₁-C₆ alkyl, and b            is 0, 1, 2, or 3; and        -   Q³ is aryl, heteroaryl, heterocyclyl, aralkyl, or            alkylene-heterocyclyl;    -   R¹ is hydrogen or alkyl;    -   Z is —(X¹)_(q)—(X²);        -   wherein X¹ is S(O)₂, C(O), or alkyl, and q is 0 or 1; and        -   X² is aryl, heteroaryl, or heterocyclyl.

In a third aspect of the present invention, there is provided apharmaceutical composition comprising: a therapeutically effectiveamount of a compound of formula (I) or (II), or a salt, solvate, or aphysiologically functional derivative thereof and one or more ofpharmaceutically acceptable carriers, diluents, and excipients.

In a fourth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being characterized bybone loss, comprising: administering to said mammal a therapeuticallyeffective amount of a compound of formula (I) or (II) or a salt, solvateor a physiologically functional derivative thereof.

In a fifth aspect of the present invention, there is provided a compoundof formula (I) or (II), or a salt, solvate, or a physiologicallyfunctional derivative thereof for use in therapy.

In a sixth aspect of the present invention, there is provided the use ofa compound of formula (I) or (II), or a salt, solvate, or aphysiologically functional derivative thereof in the preparation of amedicament for use in the treatment of a disorder characterized by boneloss.

In a seventh aspect of the present invention, there is provided a methodof treating osteoporosis including administering to said mammal atherapeutically effective amount of a compound of formula (I) or (II),or a salt, solvate or physiologically functional derivative thereof.

In an eighth aspect of the present invention, there is provided a methodof treating osteoporosis including administering to said mammaltherapeutically effective amounts of (i) a compound of formula (I) or(II), or a salt, solvate or physiologically functional derivativethereof and (ii) at least one bone building agent. The bone buildingagent may be, for example, parathyroid hormone (PTH).

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon, preferably having from one to twelve carbon atoms,optionally substituted with substituents selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, or lowerperfluoroalkyl, multiple degrees of substitution being allowed. Examplesof “alkyl” as used herein include, but are not limited to, methyl,ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl,n-pentyl, and the like.

As used herein, the term “C_(n)-C_(m) alkyl” refers to an alkyl group,as defined above, which contains the specified number of carbon atoms.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical, preferably having from one to tencarbon atoms. Alkylene groups may be optionally substituted withsubstituents selected from the group consisting of lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, and lower perfluoroalkyl.Multiple degrees of substitution are allowed. Examples of “alkylene” asused herein include, but are not limited to, methylene, ethylene,n-propylene, n-butylene, and the like.

As used herein, the term “C_(n)-C_(m) alkylene” refers to an alkylenegroup, as defined above, which contains the specified number of carbonatoms.

As used herein, the term “halogen” refers to fluorine, chlorine,bromine, or iodine.

As used herein, the term “haloalkyl” refers to an alkyl group, asdefined herein, that is substituted with at least one halogen. Examplesof branched or straight chained “haloalkyl” groups useful in the presentinvention include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, and t-butyl substituted independently with one ormore halogens, e.g., fluoro, chloro, bromo and iodo. The term“haloalkyl” should be interpreted to include such substituents asperfluoroalkyl and the like.

As used herein, the term “cycloalkyl” refers to a non-aromatic cyclichydrocarbon ring, which optionally includes an alkylene linker throughwhich the cycloalkyl may be attached. Exemplary “cycloalkyl” groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a heterocyclic ring, preferably three to twelve-membered;being either saturated or having one or more degrees of unsaturation.These heterocyclic rings contain one or more nitrogen, sulfur, and/oroxygen atoms, where N-oxides, sulfur oxides, and dioxides arepermissible heteroatom substitutions. Optionally, as used herein, theheterocyclics may be substituted with substituents selected from thegroup consisting of lower alkyl, lower haloalkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple degreesof substitution being allowed. Such a ring may be optionally fused toone or more of another “heterocyclic” ring(s) or cycloalkyl ring(s).Examples of “heterocyclic” include, but are not limited to,tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine,pyrrolidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, andthe like.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted benzene ring system fusedto one or more optionally substituted benzene rings to form, forexample, anthracene, phenanthrene, or napthalene ring systems. Exemplaryoptional substituents include lower alkyl, cycloalkyl, lower haloalkyl,lower alkoxy, aryloxy, aralkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, tetrazolyl, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, lower haloalkyl, heteroaryl, oraryl. Multiple degrees of substitution should be considered as includedwithin the present invention. Examples of “aryl” groups include, but arenot limited to, phenyl, 2-naphthyl, 1-naphthyl, and biphenyl, as well assubstituted derivatives thereof.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic aromatic ringsystem comprising two of such monocyclic five to seven membered aromaticrings. These heteroaryl rings contain one or more nitrogen, sulfur,and/or oxygen atoms, where N-oxides and sulfur oxides and dioxides arepermissible heteroatom substitutions and may be optionally substitutedwith up to three members selected from a group consisting of loweralkyl, lower haloalkyl, cycloalkyl, lower alkoxy, aryloxy, aralkoxy,lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerhaloalkyl, heteroaryl, or aryl. Multiple degrees of substitution shouldbe considered within the scope of the present invention. Examples of“heteroaryl” groups used herein include furan, thiophene, pyrrole,imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole,oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine,pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole,indazole, and substituted versions thereof.

As used herein, the term “aralkyl” refers to an aryl or heteroarylgroup, as defined herein, attached through an alkylene linker. Examplesof “aralkyl” include, but are not limited to benzyl, phenylpropyl,2-pyridylmethyl, 3-isoxazolylmethyl, 5-methyl-3-isoxazolylmethyl, and2-imidazoyly ethyl.

As used herein, the term “arylamino” refers to an aryl or heteroarylgroup, as defined herein, attached through an amino group —NR′—, whereinR′ is as defined herein.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl as defined above and the term “C_(n)-C_(m) alkoxy” refersto the group R_(a)O—, where R_(a) is C_(n)-C_(m), alkyl.

As used herein, the term “aryloxy” refers to the group R_(b)O—, whereR_(b) is aryl or heteroaryl as defined above.

As used herein the term “aralkoxy” refers to the group R_(b)R_(a)O—,where R_(a) is alkylene and R_(b) is aryl or heteroaryl, each as definedabove.

As used herein, the term “haloalkoxy” refers to the group R_(a)O—, whereR_(a) is haloalkyl as defined above and the term “C_(n)-C_(m)haloalkoxy” refers to the group R_(a)O—, where R_(a) is C_(n)-C_(m)haloalkyl as defined above.

As used herein, the term “oxo” refers to the group ═O

As used herein, the term “mercapto” refers to the group —SH.

As used herein, the term “sulfanyl” shall refer to the group —S—.

As used herein, the term “sulfenyl” shall refer to the group —S(O)—.

As used herein, the term “sulfonyl” shall refer to the group —S(O)₂—.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl as defined above.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl as defined above.

As used herein, the term “alkylsulfonyl” refers to the groupR_(a)S(O)₂—, where R_(a) is alkyl as defined above.

As used herein, the term “aminosulfonyl” refers to the group —S(O)₂NH₂.

As used herein, the term “cyano” refers to the group —CN.

As used herein the term “cyanoalkyl” refers to the group —R_(a)CNwherein R_(a) is an alkylene as defined above. Exemplary “cyanoalkyl”groups useful in the present invention include, but are not limited tocyanomethyl, cyanoethyl, and cyanopropyl.

As used herein, the term “carboxy” refers to the group —COOH.

As used herein, the term “carbamoyl” refers to the group —C(O)NH₂.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, cycloalkyl, or heterocycyll as defined herein.

As used herein, the term “aroyl” refers to the group R_(b)C(O)—, whereR_(b) is aryl as defined herein.

As used herein, the term “heteroaroyl” refers to the group R_(b)C(O)—,where R_(b) is heteroaryl as defined herein.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl as defined herein.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyloxy” refers to the group R_(b)C(O)O—,where R_(b) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” refers to the groupR_(b)C(O)O—, where R_(b) is heteroaryl as defined herein.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur, and events that do not occur.

The compounds of formulas (I) and (II) have the ability to crystallizein more than one form, a characteristic known as polymorphism, and it isunderstood that such polymorphic forms (“polymorphs”) are within thescope of formulas (I) and (II). Polymorphism generally can occur as aresponse to changes in temperature or pressure or both and can alsoresult from variations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility, and melting point.

Certain of the compounds described herein contain one or more chiralcenters, or may otherwise be capable of existing as multiplestereoisomers. The scope of the present invention includes mixtures ofstereoisomers as well as purified enantiomers or enantiomerically ordiastereomerically enriched mixtures. Also included within the scope ofthe invention are the individual isomers of the compounds represented byformula (I) and (II), as well as any wholly or partially equilibratedmixtures thereof. The present invention also covers the individualisomers of the compounds represented by the formulas above as mixtureswith isomers thereof in which one or more chiral centers are inverted.

The following embodiments refer to compounds within the scope of bothformula (I) and formula (II) as defined above unless specificallylimited by the definition of each formula or specifically limitedotherwise. It is also understood that the embodiments of the presentinvention described herein, including uses and compositions, areapplicable to both formula (I) and formula (II).

One embodiment of the present invention includes compounds of formula(I):

or a salt, solvate, or physiological functional derivatives thereof,wherein A is the group defined by (Q³)_(p)-(Q²)_(n)-(Q¹)-(Q)_(m)-,wherein Q is CH₂ and m is 0, 1, or 2, or Q is OCH₂ and m is 0 or 1, or Qis N(R³)CH₂ and m is 0 or 1, where R³ is hydrogen or C₁-C₆ alkyl;further wherein Q¹ is aryl, heteroaryl, or heterocyclyl; further whereinQ² is CH₂ and n is 0 or 1, or Q² is O and n is 0 or 1, or Q² is N(R³)and n is 0 or 1, where R³ is hydrogen or C₁-C₆ alkyl; further wherein Q³is aryl or heteroaryl and p is 0 or 1; further wherein R¹ is alkyl orcycloalkyl, said cycloalkyl may be optionally substituted with alkyl;further wherein D is O or S; further wherein R² is hydrogen or alkyl;and further wherein Z is —(X¹)_(q)—(X²); wherein X¹ is S(O)₂, C(O), or—CH₂—, and q is 0, 1, or 2; and X² is aryl, heteroaryl, or heterocyclyl.

Preferably, Q is CH₂ and m is 1. Preferably, Q¹ is aryl, heteroaryl, orheterocyclyl. More preferably, Q¹ is

Preferably, n is 0. Preferably, Q³ is aryl or heteroaryl, and p is 1.Preferably, Q³ is

More preferably, the aryl is substituted with haloalkyl. Preferably, Ais

Preferably R¹ is lower alkyl. More preferably, R¹ is t-butyl. Morepreferably, R¹ is

Preferably R² is hydrogen, methyl, or n-butyl. More preferably, R² ismethyl or n-butyl. More preferably R² is n-butyl, more preferably R² is

Preferably, Z is —(X¹)_(q)—(X²) wherein X¹ is S(O)₂; q is 1; and X² isheteroaryl or heterocyclyl. More preferably, Z is

The scope of the present invention includes the following compounds:

-   (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl    2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;-   (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl    (1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;-   (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;-   (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl    (1S)-1-{[(4-morpholinylcarbonyl)amino]acetyl}pentylcarbamate;-   (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl    (1S)-1-{[(6-fluoro-2-pyridinyl)amino]acetyl}pentylcarbamate;-   (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;-   (1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;-   (1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl    (1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;-   (1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;-   (1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl    (1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;-   (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;-   (1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;-   (1 S)-2,2-dimethyl-1-{[3-(3-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;-   (1S)-2,2-dimethyl-1-{[3-(4-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;-   (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;-   (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl    (1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;-   (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl    2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;-   (1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate; and-   (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl    (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate.

Another embodiment of the present invention includes compounds ofFormula (II):

or a salt, solvate, or pharmaceutically functional derivative thereof,wherein B is -(Q¹)_(a)-(Q²)_(b)-(Q³); further wherein Q¹ is C(O), S(O)₂,or CR²R³, where R² and R³ each are independently selected from hydrogenor C₁-C₆ alkyl, and a is 0, 1, 2, or 3; Q² is O, S, NR², or CR²R³, whereR² and R³ each are independently selected from hydrogen or C₁-C₆ alkyl,and b is 0, 1, 2, or 3; and Q³ is aryl, heteroaryl, heterocyclyl,aralkyl, or alkylene-heterocyclyl; R¹ is hydrogen or alkyl; Z is—(X¹)_(q)—(X²), wherein X¹ is S(O)₂, C(O), or alkyl, and q is 0 or 1;and X² is aryl, heteroaryl, or heterocyclyl.

Stereochemically, compounds of Formula (II) preferably are:

Further, preferably, a is 0; b is 0; and Q³ is a heterocyclyl. Morepreferably, B is

Preferably R¹ is hydrogen, methyl, or n-butyl. More preferably, R¹ ismethyl or n-butyl. More preferably R¹ is n-butyl, more preferably R¹ is

Preferably, Z is —(X¹)_(q)—(X²), where X¹ is S(O)₂; q is 1; and X² isheteroaryl. More preferably Z is

Another aspect of the present invention includes a pharmaceuticalcomposition including a therapeutically effective amount of a compoundof the present invention and one or more of a pharmaceuticallyacceptable carrier, diluent, or excipient.

Another aspect of the present invention includes a method for treating adisorder characterized by inappropriate capthesin K activity byadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of the present invention. Such method involves thetreatment or prophylaxis of a disorder that is characterized by enhancedbone turnover that can ultimately lead to fracture throughadministration of an effective amount of a compound of the presentinvention.

Another aspect of the present invention includes a method for thepreparation of a medicament for the treatment of a disorder, thedisorder characterized by bone loss. Preferably, such method includescombining a compound of the present invention with one or more of apharmaceutically acceptable carrier, diluent, or excipient.

Another aspect of the present invention includes a method for treatingosteoporosis by administering to a mammal in need thereof a compound ofthe present invention. The method of treating osteoporosis can includeadministration of at least one bone building agent as well.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention; for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives will be clear to those skilled in the art,without undue experimentation, and with reference to the teaching ofBurger's Medicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula I or II), or a salt or physiologically functional derivativethereof) and a solvent. Such solvents, for the purpose of the invention,should not interfere with the biological activity of the solute.Non-limiting examples of suitable solvents include, but are not limitedto water, methanol, ethanol, and acetic acid. Preferably the solventused is a pharmaceutically acceptable solvent. Non-limiting examples ofsuitable pharmaceutically acceptable solvents include water, ethanol,and acetic acid. Most preferably the solvent used is water.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention. Salts of the compounds of the present invention may compriseacid addition salts derived from a nitrogen on a substituent in thecompound of formula (I) or formula (II). Representative salts includeacetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexykesorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, potassium, salicylate, sodium, stearate, subacetate,succinate, tannate, tartrate, teoclate, tosylate, triethiodide,trimethylammonium, and valerate salts. Other salts, which are notpharmaceutically acceptable, may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I) or formula (II), as well as salts,solvates and physiological functional derivatives thereof, may beadministered as the raw chemical, it is possible to present the activeingredient as a pharmaceutical composition. Accordingly, the inventionfurther provides pharmaceutical compositions that includetherapeutically effective amounts of compounds of the formula (I) or(II) and salts, solvates and physiological functional derivativesthereof, and one or more pharmaceutically acceptable carriers, diluents,or excipients. The compounds of formula (I) or (II) and salts, solvatesand physiologically functional derivatives thereof, are as describedabove. The carrier(s), diluent(s) or excipient(s) must be acceptable, inthe sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient of the pharmaceuticalcomposition. In accordance with another aspect of the invention there isalso provided a process for the preparation of a pharmaceuticalformulation including admixing a compound of the formula (I) or (II), orsalts, solvates and physiological functional derivatives thereof, withone or more pharmaceutically acceptable carriers, diluents orexcipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of acompound of the formula (I) or (II), depending on the condition beingtreated, the route of administration, and the age, weight, and conditionof the patient. Preferred unit dosage formulations are those containinga daily dose or sub-dose, as herein above recited, or an appropriatefraction thereof, of an active ingredient. Such pharmaceuticalformulations may be prepared by any of the methods well known in thepharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by an oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions, each with aqueous or non-aqueousliquids; edible foams or whips; or oil-in-water liquid emulsions orwater-in-oil liquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Generally, powders are prepared bycomminuting the compound to a suitable fine size and mixing with anappropriate pharmaceutical carrier such as an edible carbohydrate, as,for example, starch or mannitol. Flavorings, preservatives, dispersingagents, and coloring agents can also be present.

Capsules are made by preparing a powder, liquid, or suspension mixtureand encapsulating with gelatin or some other appropriate shell material.Glidants and lubricants such as colloidal silica, talc, magnesiumstearate, calcium stearate or solid polyethylene glycol can be added tothe mixture before the encapsulation. A disintegrating or solubilizingagent such as agar-agar, calcium carbonate or sodium carbonate can alsobe added to improve the availability of the medicament when the capsuleis ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Examples of suitable binders include starch, gelatin,natural sugars such as glucose or beta-lactose, corn sweeteners, naturaland synthetic gums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants useful in these dosage forms include, for example, sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like. Tablets are formulated, for example, by preparing a powdermixture, granulating or slugging, adding a lubricant and disintegrant,and pressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials, and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs can be broken into granules.The granules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material, and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared, for example, bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated generally by dispersing the compound in anon-toxic vehicle. Solubilizers and emulsifiers such as ethoxylatedisostearyl alcohols and polyoxy ethylene sorbitol ethers; preservatives;flavor additives such as peppermint oil, or natural sweeteners,saccharin, or other artificial sweeteners; and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I) or (II) and salts, solvates andphysiological functional derivatives thereof, can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, or phosphatidylcholines.

The compounds of formula (I) or (II) and salts, solvates andphysiologically functional derivatives thereof may also be delivered bythe use of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug; for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986), incorporated herein by reference as related to such deliverysystems.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration, where thecarrier is a solid, include a coarse powder having a particle size forexample in the range 20 to 500 microns. The powder is administered inthe manner in which snuff is taken, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavoring agents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors. For example, the age andweight of the animal, the precise condition requiring treatment and itsseverity, the nature of the formulation, and the route of administrationare all factors to be considered. The therapeutically effective amountultimately should be at the discretion of the attendant physician orveterinarian. Regardless, an effective amount of a compound of formula(I) or (II) for the treatment of osteoporosis, generally, should be inthe range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day.More usually the effective amount should be in the range of 1 to 10mg/kg body weight per day. Thus, for a 70 kg adult mammal the actualamount per day would usually be from 70 to 700 mg. This amount may begiven in a single dose per day or in a number (such as two, three, four,five, or more) of sub-doses per day such that the total daily dose isthe same. An effective amount of a salt or solvate, or physiologicallyfunctional derivative thereof, may be determined as a proportion of theeffective amount of the compound of formula (I) or (II) per se. Similardosages should be appropriate for treatment of the other conditionsreferred to above.

The compounds of the present invention and their salts and solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in osteoporosis therapy,combination with other osteoporosis therapeutic agents is envisaged.Combination therapies according to the present invention thus comprisethe administration of at least one compound of formula (I) or (II) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof, and the use of at leastone other osteoporosis treatment method. Preferably, combinationtherapies according to the present invention comprise the administrationof at least one compound of formula (I) or (II) or a pharmaceuticallyacceptable salt or solvate thereof, or a physiologically functionalderivative thereof, and at least one other osteoporosis treatment agent,preferably a bone building agent. The compound(s) of formula (I) or (II)and the other pharmaceutically active agent(s) may be administeredtogether or separately and, when administered separately, this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) or (II) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect. Theadministration in combination of a compound of formula (I) or (II) orsalts, solvates, or physiologically functional derivatives thereof withother osteoporosis treatment agents may be in combination byadministration concomitantly in (1) a unitary pharmaceutical compositionincluding both compounds or (2) separate pharmaceutical compositionseach including one of the compounds. Alternatively, the combination maybe administered separately in a sequential manner wherein oneosteoporosis treatment agent is administered first and the other secondor vice versa. Such sequential administration may be close in time orremote in time.

A preferred additional osteoporosis treatment agent is a bone building(anabolic) agent. Bone building agents can lead to increases inparameters such as bone mineral density greater than those than can beachieved with anti-resorptive agents. In some cases, such anabolicagents can increase trabecular connectivity leading to greaterstructural integrity of the bone. A combination therapy composed of abone forming agent with an anti-resorptive drug such as a cathepsin Kinhibitor could provide even greater efficacy than treatment with eitheragent alone.

The present invention is directed to methods of regulating, modulating,or inhibiting cathepsin K for the prevention and/or treatment ofdisorders related enhanced bone turnover, which can ultimately lead tofracture. In particular, the compounds of the present invention can alsobe used in the treatment of osteoporosis. Furthermore, the compounds ofthe present invention can be used to provide additive or synergisticeffects with existing osteoporosis therapies.

The present invention thus also provides compounds of formula (I) or(II) and pharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders mediated byenhanced bone turnover which can ultimately lead to fracture.

The present invention also provides compounds of formula (I) or (II) andpharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders characterized bybone loss or characterized by excessive cartilage or matrix degradation.

The compounds of the present invention are also useful in the treatmentof one or more diseases afflicting mammals that are characterized bypotential involvement of cathepsin K in autoimmune diseases such asrheumatoid arthritis, osteoathritis, neoplastic diseases, parasiticdiseases, and atherosclerosisis.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder mediated by enhanced bone turnover thatcan ultimately lead to fracture, which includes administering to saidsubject an effective amount of a compound of formula (I) or (II) or apharmaceutically acceptable salt, solvate, or a physiologicallyfunctional derivative thereof.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder characterized by bone loss, whichincludes administering to said subject an effective amount of a compoundof formula (I) or (II) or a pharmaceutically acceptable salt, solvate,or a physiologically functional derivative thereof. In a preferredembodiment, the disorder is osteoporosis.

A further aspect of the invention provides a method of treatment of amammal suffering from osteoporosis, which includes administering to saidsubject an effective amount of a compound of formula (I) or (II) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof.

A further aspect of the present invention provides the use of a compoundof formula (I) or (II), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of a disordercharacterized by enhanced bone turnover that can ultimately lead tofracture. In a preferred embodiment, the disorder is osteoporosis.

A further aspect of the present invention provides the use of a compoundof formula (I) or (II), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of a disordercharacterized by bone loss. In a preferred embodiment, the disorder isosteoporosis. A further aspect of the present invention provides the useof a compound of formula (I) or (II), or a pharmaceutically acceptablesalt or solvate thereof, or a physiologically functional derivativethereof, in the preparation of a medicament for the treatment ofosteoporosis. In another embodiment, therapeutically effective amountsof the compounds of formula (I) or (II) or salts, solvates orphysiologically derived derivatives thereof and at least one bonebuilding agent may be administered in combination to a mammal fortreatment of osteoporosis.

The mammal requiring treatment with a compound of the present inventionis typically a human being.

The compounds of this invention may be made by a variety of methods,including standard synthetic methods. Any previously defined variablewill continue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

Compounds of general formula (I) or formula (II) may be prepared bymethods known in the art of organic synthesis as set forth in part bythe following synthetic schemes. Generally, the following schemes areillustrated using compounds of formula (I), but it is recognized thatsuch schemes are easily adaptable by the skilled artisan to prepareother compounds of formula (II). It is also recognized that in all ofthe schemes described below, it is well understood that protectinggroups for sensitive or reactive groups are employed where necessary inaccordance with general principles of synthetic chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups inOrganic Synthesis, John Wiley & Sons). These groups are removed at aconvenient stage of the compound synthesis using methods that arereadily apparent to those skilled in the art. The selection of processesas well as the reaction conditions and order of their execution shall beconsistent with the preparation of compounds of formula (I) or (II).Those skilled in the art will recognize if a stereocenter exists incompounds of formula (I) or (II). Accordingly, the present inventionincludes all possible stereoisomers and includes not only racemiccompounds but the individual enantiomers as well. When a compound isdesired as a single enantiomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be effected by any suitable method known in theart. See, for example, Stereochemistry of Organic Compounds by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Compounds of formula (I) and (II), can be prepared according to thesynthetic sequences shown in Schemes I and II, which are furtherdetailed in the Examples section following.

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be usedthroughout the present specification:

g (grams);

L (liters);

μL (microliters);

M (molar);

h (hour(s));

MHz (megahertz);

mmol (millimoles);

min (minutes);

mp (melting point);

T_(r) (retention time);

MeOH (methanol);

TEA (triethylamine);

TFAA (trifluoroacetic anhydride);

DMSO (dimethylsulfoxide);

DME (1,2-dimethoxyethane);

DCE (dichloroethane);

mg (milligrams);

mL (milliliters);

psi (pounds per square inch);

mM (millimolar);

Hz (Hertz);

mol (moles);

RT (room temperature);

TLC (thin layer chromatography);

RP (reverse phase);

i-PrOH (isopropanol);

TFA (trifluoroacetic acid);

THF (tetrahydrofuran);

EtOAc (ethyl acetate);

DCM (dichloromethane);

DMF (NN-dimethylformamide);

DMPU (N,N′-dimethylpropyleneurea);

IBCF (isobutyl chloroformate);

HOSu (N-hydroxysuccinimide);

mCPBA (meta-chloroperbenzoic acid);

EDC (ethylcarbodiimide hydrochloride);

BOC (tert-butyloxycarbonyl);

DCC (dicyclohcxylcarbodiimide);

Ac (acetyl);

TMSE (2-(trimethylsilyl)ethyl);

TIPS (triisopropylsilyl);

DMAP (4-dimethylaminopyridine);

HPLC (high pressure liquid chromatography);

BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);

TBAF (tetra-n-butylammonium fluoride);

Et (ethyl);

CDI (1,1-carbonyldiimidazole);

HOAc (acetic acid);

HOBT (1-hydroxybenzotriazole);

FMOC (9-fluorenylmethoxycarbonyl);

CBZ (benzyloxycarbonyl);

atm (atmosphere);

TMS (trimethylsilyl);

TBS (t-butyldimethylsilyl);

Me (methyl);

tBu (tert-butyl).

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in degrees Centigrade (° C.). All reactionswere conducted under an inert atmosphere at room temperature unlessotherwise noted.

¹H-NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, or a General Electric QE-300. Chemicalshifts are expressed in parts per million (ppm, δunits). Couplingconstants are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated by: s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), br (broad).

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA,JOEL SX-102, or a SCIEX-APIiii spectrometer; high resolution MS wereobtained using a JOEL SX-102A spectrometer. All mass spectra were takenunder electrospray ionization (ESI), chemical ionization (CI), electronimpact (El) or by fast atom bombardment (FAB) methods. Infrared (IR)spectra were obtained on a Nicolet 510

FT-IR spectrometer using a 1-mm NaCl cell. All reactions were monitoredby thin-layer chromatography on 0.25 mm E. Merck silica gel plates(60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid,iodine, iodoplatinate(potassium), permanganate(potassium), orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck). Optical rotations were obtained usinga Perkin Elmer Model 241 Polarimeter. Melting points were determinedusing a Mel-Temp II apparatus and are uncorrected.

The following examples describe the syntheses of compounds of Formula(I) and (II) as well as intermediates particularly useful in thesynthesis of compounds of Formula (I) and (II):

Example 1 Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

Example 1a Preparation of (S)-2-hydroxy-3,3-dimethylbutanoic Acid

To a solution of 30.0 g (0.229 mol) of L-tert-leucine in 345 mL of 1 Nsulfuric acid, cooled to 0° C., was added over 2 h a solution of 23.7 g(0.343 mol) of sodium nitrite in 83 mL of water. The temperature wasmaintained below 5° C. during the addition, and the mixture was thenrefrigerated for 24 h. The solution was then extracted with 150 mL ofether (3×) and the extract was washed with 100 mL of saturated aqueoussodium chloride. The extract was dried over anhydrous magnesium sulfate,filtered, and concentrated to afford 19.5 g (65%) of a pale yellow oil.The crude product was taken to the next step. ¹H-NMR (300 MHz, CDCl₃): δ3.91 (s, 1H), 1.01 (s, 9H).

Example 1b Preparation of (2S)-3,3-dimethyl-1,2-butanediol

To a solution of 18.0 g (0.136 mol) of(S)-2-hydroxy-3,3-dimethylbutanoic acid in 150 mL of ether, cooled to 0°C., was added 272 mL (272 mmol) of a 1.0 M solution of lithium aluminumhydride in tetrahydrofuran over a period of 30 min. The reaction mixturewas then warmed to room temperature and stirred for 16 h. To thereaction mixture was added 100 mL of 50% concentrated hydrochloric acid.The layers were separated, the aqueous layer was extracted with 200 mLof ether (3×), and the extract was dried over anhydrous magnesiumsulfate. After filtration and concentration, the crude product waspurified by column chromatography on silica gel with hexane:ethylacetate (1:9) as the eluent to afford 10.2 g (63%) of(2S)-3,3-dimethyl-1,2-butanediol as a colorless solid. ¹H-NMR (300 MHz,CDCl₃): δ 3.74 (dd, J=10 Hz, J=3 Hz, 1H), 3.48 (t, J=10 Hz, 1H), 3.36(dd, J=10 Hz, J=3 Hz, 1H), 2.70 (br s, 2H), 0.91 (s, 9H).

Example 1c Preparation of (2S)-2-hydroxy-3,3-dimethylbutyl4-methylbenzenesulfonate

To 6.65 g (56 mmol) of (2S)-3,3-dimethyl-1,2-butanediol in 13 mL ofpyridine at 0° C. was added dropwise a solution of 10.68 g (56 mmol) ofp-toluenesulfonyl chloride in 20 mL of pyridine. The solution wasmaintained at 0° C. for 5 h and then let warm to ambient temperature.After being stirred overnight, the mixture was concentrated, and theresidue was taken up in 200 mL of diethyl ether. The ether solution waswashed with 50 mL of 1N hydrochloric acid, 50 mL of saturated aqueoussodium bicarbonate, and 50 mL of water, dried over anhydrous magnesiumsulfate, and concentrated. The residue was purified by silica gelchromatography eluting with ethyl acetate:hexanes (3.5:6.5) to give 13 g(85%) of (2S)-2-hydroxy-3,3-dimethylbutyl 4-methylbenzenesulfonate.¹H-NMR (300 MHz, DMSO-d₆): δ 7.79 (d, J=8 Hz, 2H), 7.47 (d, J=8 Hz, 2H),5.11 (br s, 1H), 4.08 (dd, J=10 Hz, J=3 Hz, 1H), 3.76 (dd, J=10 Hz, J=8Hz, 1H), 3.23 (d, J=8 Hz, 1H), 2.41 (s, 3H), 0.76 (s, 9H). ES-LCMS m/z273 (M+H), 295 (M+Na).

Example 1d Preparation of (S)-3,3-dimethyl-1,2-epoxybutane

To 20.05 g (73.7 mmol) of (2S)-2-hydroxy-3,3-dimethylbutyl4-methylbenzenesulfonate in 300 mL of methanol at 0° C. was addeddropwise 75.2 mL (75.2 mmol) of 1M sodium hydroxide, and the mixture wasstirred for 30 min. It was then diluted with 10 mL of saturatedpotassium dihydrogen phosphate, and poured into 1400 mL of water. Themixture was extracted three times with 50 mL of pentane. The extractswere combined and dried over anhydrous magnesium sulfate, and thepentane was distilled off to afford 7.94 g (83%) of(S)-3,3-dimethyl-1,2-epoxybutane with 0.4 mole equivalents of residualpentane. ¹H-NMR (300 MHz, DMSO-d₆): δ 2.69 (dd, J=4 Hz, J=3 Hz, 1H),2.52-2.57 (m, 2H), 0.85 (s, 9H).

Example 1e Preparation of 3-[4-(Trifluoromethyl)phenyl]-1H-pyrazole

First, 3.18 g (79.4 mmol) of a 60% sodium hydride suspension in mineraloil was added in portions to a solution of 9.96 g (52.9 mmol) of4-trifluoromethylacetophenone and 12.6 mL (158.76 mmol) of ethyl formatein 75 mL of anhydrous tetrahydrofuran at 0° C. The mixture was allowedto reach ambient temperature, at which an exothermic reaction occurred,which subsided in 5 min. After 1 h, the mixture was concentrated and theresidue was triturated with diethyl ether to provide a tan solid in twocrops. The solid was suspended in 1N hydrochloric acid and the resultingbright yellow solid was filtered and washed with water. The solid wasdissolved in 150 mL of methanol and stirred at room temperature with 4.7mL (96.9 mmol) of hydrazine hydrate for 3 h. Solvent was evaporated andthe resulting solid was suspended in water, stirring for 18 h. The solidwas filtered, washed with water, and dried under vacuum to provide 8.9 g(80%) of 3-[4-(trifluoromethyl)phenyl]-1H-pyrazole as a yellow solid.¹H-NMR (DMSO-d₆): δ 13.05 (br s, 1H), 7.99 (d, J=8 Hz, 2H), 7.8 (br s,1H), 7.71 (d, J=8 Hz, 2H), 6.81 (s, 1H); ES-LCMS m/z 213 (M+H).

Example 1f Preparation of(2S)-3,3-Dimethyl-1-{3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol

A mixture of 4.11 g (19.4 mmol) of3-[4-(trifluoromethyl)phenyl]-1H-pyrazole, 2.0 g (19.9 mmol) of(S)-3,3-dimethyl-1,2-epoxybutane, 3.1 mL (22.3 mmol) of triethylamine,and 10 mL of isopropyl alcohol was placed in a sealed tube and heated at85° C. for 48 h. Solvent was evaporated and the residue was purified bysilica gel chromatography eluting with ethyl acetate:hexanes (1:7) togive 2.92 g (49%) of(2S)-3,3-dimethyl-1-{3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanolas a pale yellow solid and 0.4 g (7%) of its isomer(2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol.Data for(2S)-3,3-dimethyl-1-{3-[4-(tifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol:¹H-NMR (DMSO-d₆): δ 7.96 (d, J 8 Hz, 2H), 7.75 (s, 1H), 7.69 (d, J=8 Hz,2H), 6.76 (d, J=2 Hz, 1H), 4.86 (d, J=6 Hz, 1H), 4.26 (dd, J=14 Hz, J=2Hz, 1H), 3.88 (dd, J=14 Hz, J=10 Hz, 1H), 3.45-3.50 (m, 1H), 0.88 (s,9H); ES-LCMS m/z 313 (M+H). Data for(2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol:¹H-NMR (DMSO-d₆): δ 7.87 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H), 7.52 (d,J=2 Hz, 1H), 6.42 (d, J=2 Hz, 1H), 5.01 (d, J=6 Hz, 1H), 4.10 (dd, J=14Hz, J=2 Hz, 1H), 3.92 (dd, J=14 Hz, J=10 Hz, 1H), 3.62-3.67 (m, 1 H),0.82 (s, 9H); ES-LCMS m/z 313 (M+H).

Example 1g Preparation of (1S)-2,2-Dimethyl-1-({3-[4-(trifluoromethyl)phenyl-]1H-pyrazol-1-yl}methyl)propyl4-nitrophenyl Carbonate

To a solution of 2.56 g (8.19 mmol) of(2S)-3,3-dimethyl-1-{3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanoland 1.54 g (19.6 mmol) of pyridine in 29 mL of anhydrous dichloromethanewas added 1.98 g (9.83 mmol) of p-nitrophenyl chloroformate. The mixturewas stirred at ambient temperature for 18 h. It was washed with 5%citric acid and then stirred with ammonium hydroxide:water (1:4) for 15min. The organic phase was washed with sodium bicarbonate:water, driedwith sodium sulfate, and concentrated to provide 3.7 g (94%) of(1S)-2,2-Dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl-4-nitrophenylcarbonateas a pale yellow solid. ¹H-NMR (DMSO-d₆): δ 8.10 (d, J=9 Hz, 2H), 7.97(d, J=8 Hz, 2H), 7.91, (d, J=2 Hz, 1H), 7.70 (d, J=8 Hz, 2H), 7.21 (d,J=9 Hz, 2H), 6.85 (d, J=2 Hz, 1H), 4.87 (dd, J=10 Hz, J=2 Hz, 1H), 4.61(dd, J=14 Hz, J=2 Hz, 1H), 4.33 (dd, J=14 Hz, J=10 Hz, 1H), 1.02 (s,9H); ES-LCMS m/z 478 (M+H).

Example 1h Preparation of tert-butyl 2-oxiranylmethylcarbamate

To a solution of 28.9 g (184 mmol) of tert-butyl allylcarbamate in 400mL of dichloromethane was added 103 g (460 mmol) of 77%3-chloroperoxybenzoic acid at room temperature. The reaction mixture wasstirred at room temperature overnight. The solid was filtered and thefiltrate was concentrated. The residue was taken up in diethyl ether andwashed with 5% sodium hydrosulfite (3×), saturated sodium bicarbonate(3×), brine (3×), and dried over anhydrous magnesium sulfate. Removal ofsolvent gave 21 g (66%) of tert-butyl 2-oxiranylmethylcarbamate as aliquid. ¹H-NMR (400 MHz, CDCl₃): δ 4.73 (br s, 1H), 3.53 (br s, 1H),3.21 (m, 1H), 3.08 (br s, 1H), 2.77 (t, J=4 Hz, 1H), 2.58 (m, 1H), 1.43(s, 9H).

Example 1i Preparation of tert-butyl 2-hydroxy-3-[(2pyridinylsulfonyl)amino]propylcarbamate

First, 21 g (121 mmol) of tert-butyl 2-oxiranylmethylcarbamate wasdissolved in 90 mL of dimethylformamide and 11.8 g (182 mmol) of sodiumazide was added. The reaction mixture was stirred at 65° C. overnight.The dimethylformamide was removed and ether was added. The ether layerwas washed with brine (3×), dried over anhydrous magnesium sulfate, andconcentrated. The residue was dissolved in 50 mL of methanol andhydrogenated with 2 g of 10% palladium on carbon under 45 psi ofhydrogen gas at room temperature overnight. The catalyst was removed byfiltration and the filtrate was concentrated. The residue was dissolvedin 30 mL of dichloromethane, and 17.7 mL (17.7 mmol) of 1M2-pyridinylsulfonyl chloride in dichloromethane and 3.8 mL (21.8 mmol)of N,N-diisopropylethylamine were added. The reaction mixture wasstirred at room temperature overnight. After removal of solvent,purification by column chromatography with hexane:ethyl acetate (1:2) aseluant gave 350 mg (0.9%) of tert-butyl2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate. ¹H-NMR (300 MHzCDCl₃): δ 8.72 (d, J=6 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.97 (t, J=8 Hz,1H), 7.55 (m, 1H), 6.10 (br s, 1H), 5.11 (br s, 1H), 4.33 (d, J=5 Hz,1H), 3.81 (m, 1H), 3.36-3.20 (m, 4H), 1.44 (s, 9H). ES-LCMS: 332 (M+H).

Example 1j Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To 78.7 mg (237.7 μmol) of tert-butyl2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate in 2.4 mL ofdioxane at room temperature was added 3.0 mL (11.88 mmol) of a 4 Msolution of hydrogen chloride in dioxane.

The mixture was stirred for 2 h, concentrated, and dried under vacuum.The residue was then dissolved in 2.0 mL of dimethylformamide. Thissolution was added to 108.1 mg (226.4 μmol) of 4-nitrophenyl(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propylcarbonate in 2.5 mL of dimethylformamide. This was followed by theaddition of 157.8 μL (905.7 μmol) of N,N-diisopropylethylamine, and thereaction mixture was stirred for 16 h at room temperature. The solutionwas concentrated, saturated sodium bicarbonate was added, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with saturated sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby silica gel column chromatography eluting with an ethylacetate:hexanes solution (7:3) to give 90.8 mg (63%) of a mixture ofalcohols. The alcohols were dissolved in 3.7 mL of dichloromethane atroom temperature and 97.4 mg (229.8 μmol) of Dess-Martin periodinane wasadded. The reaction mixture was stirred for 120 min, and then pouredinto saturated sodium metabisulfite. Following subsequent neutralizationwith saturated sodium bicarbonate, the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography eluting with an ethyl acetate:hexanes solution(4:1). The sample was further purified by HPLC using a Waters SymmetryC18 19 mm×150 mm column with 7 μm packing eluted with a five minutegradient of 30%-70% acetonitrile in water. The mobile phase contained a0.1% trifluoroacetic acid modifier. This purification gave 29.0 mg (28%)of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate.R_(f)=0.35 (4:1 ethyl acetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆): δ8.65 (d, J=5 Hz, 1H), 8.20 (s, 1H), 8.03 (t, J=8 Hz, 1H), 7.96 (d, J=8Hz, 2H), 7.88 (d, J=8 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8 Hz, 2H), 7.60(dd, J=8 Hz, J=5 Hz, 1H), 6.91 (br s, 1H), 6.70 (d, J=2 Hz, 1H), 4.85(d, J=6 Hz, 1H),4.45 (d, J=11 Hz, 1H),4.20(dd, J=14 Hz, J=8 Hz, 1H),3.94(d, J=6 Hz, 2H), 3.85 (d, J=5 Hz, 2H), 0.97 (s, 9H); HRMS C₂₅H₂₉F₃N₅O₅Sm/z 568.1842 (M+H)_(cal); 568.1873 (M+H)_(Obs).

Example 2 Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl-]1H-pyrazol1-yl}methyl)propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamateExample 2a Preparation of tert-butyl (1S)-1-methyl-2-oxoethylcarbamate

To a solution of 10.7 g (57.0 mmol) of(2S)-2-[(tert-butoxycarbonyl)amino]propanoic acid in 200 mL ofdichloromethane at 0° C. was added 12.0 g (74.1 mmol) ofcarbonyldiimidazole, 10.39 mL (74.1 mmol) of triethylamine, and 7.08 g(74.1 mmol) of N,O-dimethylhydroxylamine hydrochloride. The reactionmixture was warmed to room temperature and left stirring for 16 h.Diethyl ether was then added, followed by the addition of 10%hydrochloric acid. The layers were separated, and the organic layer wasthen washed with saturated sodium bicarbonate solution, dried overanhydrous magnesium sulfate and concentrated under vacuum to afford 7.05g of the crude product. Then, 7.05 g (30.4 mmol) of the crude tert-butyl(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethylcarbamate was dissolvedin 109 mL of tetrahydrofuran and cooled to 0° C. A 1.0 M solution of45.6 mL (45.6 mmol) of lithium aluminum hydride in tetrahydrofuran wasthen added gradually over 20 min. After stirring for 30 min, 10% citricacid solution was added. and the reaction mixture was stirred foranother 5 min. The reaction mixture was diluted with diethyl ether andthe layers were separated. The organic layer was dried over anhydrousmagnesium sulfate and concentrated under vacuum to afford 5.25 g (>99%)of tert-butyl (1S)-1-methyl-2-oxoethylcarbamate, which was carried intothe next step directly. ¹H-NMR (300 MHz, CDCl₃) δ 9.58 (s, 1H), 5.15 (m,1H), 4.25 (m, 1H), 1.35 (s, 9H), 1.27 (d, J=7 Hz, 3H).

Example 2b Preparation of tert-butyl(1S,2S)-3-amino-2-hydroxy-1-methylpropylcarbamate & tert-butyl(1S,2R)-3-amino-2-hydroxy-1-methylpropylcarbamate

To a solution of 5.25 g (30.4 mmol) of tert-butyl(1S)-1-methyl-2-oxoethylcarbamate in 30 mL of methanol at 0° C. wasadded 2.18 g (33.4 mmol) of potassium cyanide, followed by 1.74 mL (33.4mmol) of acetic acid. The reaction mixture was warmed to roomtemperature, left stirring for 16 h, and then filtered and concentratedunder vacuum. The residue was dissolved in 80 mL of acetic acid, and 0.8g of platinum oxide on carbon was added. The reaction mixture was thenstirred under 40 psi of hydrogen for 4 h. The catalyst was filtered offover celite, and the filtrate was washed with methanol and concentratedto afford 3.06 g (49%) of tert-butyl(1S,2S)-3-amino-2-hydroxy-1-methylpropylcarbamate & tert-butyl(1S,2R)-3-amino-2-hydroxy-1-methylpropylcarbamate. ¹H-NMR (300 MHz,DMSO-d₆): δ 6.74, 6.59 (d, J=8 Hz, 1H), 3.61-3.38 (m, 3H), 2.80 (m, 1H),2.51 (m, 2H), 1.45 (br s, 1H), 1.38 (s, 9H), 0.97 (m, 3H). GC-MS m/z 205(M+H).

Example 2c Preparation of tert-butyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate& tert-butyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To a solution of 3.06 g (15.0 mmol) of tert-butyl(1S,2S)-3-amino-2-hydroxy-1-methylpropylcarbamate & tert-butyl(1S,2R)-3-amino-2-hydroxy-1-methylpropylcarbamate in 100 mL ofdichloromethane was added 3.78 g (45.0 mmol) of sodium bicarbonate and50 mL of water. The reaction mixture was cooled to 0° C. and 16.5 mL(16.5 mmol) of a 1.0 M solution of 2-pyridinesulfonyl chloride indichloromethane was added gradually over 20 min. The reaction mixturewas stirred at room temperature for 16 h. The layers were then separatedand the organic layer was dried over anhydrous magnesium sulfate, andconcentrated under vacuum to afford the crude product. This product waspurified via silica gel chromatography eluting with ethyl acetate:hexane(8:2) to afford 2.0 g (34%) of tert-butyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate& tert-butyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamateas a pale yellow oil. ¹H-NMR (300 MHz, CDCl₃): δ 8.72 (m, 1H), 8.07-7.92(m, 2H), 7.51 (m, 1H), 6.25, 6.08 (2br s, 1H), 4.83-4.64 (m, 2H),3.74-3.47 (m, 3H), 3.27-3.19 (m, 1H), 1.23, 1.22 (2s, 9H), 1.12 (m, 3H).

Example 2d Preparation of (1S)-2,2-dimethyl-1-(553-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To a solution of 0.101 g (0.29 mmol) of tert-butyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate& tert-butyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamatein 2 mL of dioxane was added 2.0 mL of a 4.0 M solution of hydrochloricacid in dioxane. The reaction mixture was stirred for 30 min, and thenconcentrated. This residue was dissolved in 3.0 mL of dimethylformamideand this solution was added to 0.14 g (0.29 mmol) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl4-(nitro)phenyl carbonate and 1.5 mL (0.87 mmol) ofdiisopropylethylamine. The reaction mixture was stirred at roomtemperature for 16 h. A saturated solution of sodium bicarbonate wasthen added, followed by diethyl ether. The layers were separated, andthe organic layer was dried over anhydrous magnesium sulfate, andconcentrated under vacuum to afford the crude product. This crudeproduct was purified via silica gel chromatography eluting with ethylacetate:hexane (1:1) to afford 0.138 g (81%) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamateas a colorless oil. ¹H-NMR (300 MHz, CDCl₃): δ 8.64 (m, 1H), 7.98-7.88(m, 5H), 7.64-7.47 (m, 4H), 6.60 (s, 1H), 5.01-4.81 (m, 3H), 4.46, 4.42(2s br, 1H), 4.25-4.17 (m, 2H), 3.59-3.44 (m, 2H), 3.14 (m, 1H), 1.00(m, 12H); LC-MS 584 (M+H).

Example 2e Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To a solution of 0.130 g (0.22 mmol) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamatein 2.0 mL of dichloromethane was added 0.020 g (0.24 mmol) of sodiumbicarbonate and 0.11 g (0.26 mmol) of Dess-Martin periodinane. Thereaction mixture was stirred for 15 min and then purified via silica gelchromatography eluting with ethyl acetate:hexane (7:3) to afford 0.078 g(59%) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamateas a colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ 8.58 (m, 1H), 7.98-7.89(m, 4H), 7.63 (m, 2H), 7.46 (m, 2H), 6.65 (s, 1H), 5.56 (m, 1H), 1.05(s, 9H), 5.24 (d, J=7 Hz, 1H), 4.98 (m, 1H), 4.44 (m, 1H), 4.34-4.12 (m,4H), 1.12 (d, J=7 Hz, 3H); LC-MS m/z 582 (M+H).

Example 3 Preparation of(1S)-2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 3a Preparation of tert-butyl(1S)-1-{[methoxy(methyl)amino]carbonyl}pentylcarbamate

To a stirred solution of 27.8 g (120.0 mmol) of N-Boc-L-Norleucine in150 mL of dichloromethane at −40° C. was added a solution of 18.4 mL(151.5 mmol) of 1-methylpiperidine in 40 mL of dichloromethane over 20min. Then, 13.9 mL (145.4 mmol) of ethyl chloroformate in 40 mL ofdichloromethane was added over 30 min and the reaction mixture wasstirred at −40° C. for 2.5 h. A solution of 14.2 g (145.4 mmol) ofN,O-dimethylhydroxylamine hydrochloride and 18.4 mL (151.5 mmol) of1-methylpiperidine in 90 mL of dichloromethane was added over 45 min,then the reaction mixture was allowed to slowly warm to room temperatureand was stirred for 18 h. It was then washed with 100 mL of water, 100mL of 1% hydrochloric acid (2×), 100 mL of saturated aqueous sodiumbicarbonate, and dried over anhydrous magnesium sulfate. Concentrationin vacuo afforded 35.0 g (quantitative yield) of crude tert-butyl(1S)-1-{[methoxy(methyl)amino]carbonyl}pentylcarbamate as a thick oil.¹H-NMR (400 MHz, DMSO-d₆): δ 6.94 (d, J=8 Hz, 1H), 4.35-4.25 (m, 1H),3.68 (s, 3H), 3.05 (s, 3H), 1.52-1.36 (m, 2H), 1.32 (s, 9H), 1.30-1.14(m, 4H), 0.80 (t, J=6 Hz, 3H).

Example 3b Preparation of tert-butyl (1S)-1-formylpentylcarbamate

To a stirred solution of 54.0 mL (180.0 mmol) of 65 wt % bis(2-methoxyethoxy) aluminum hydride in toluene in 100 mL of toluene at−20° C. was added a solution of 35.0 g (120.0 mmol) of tert-butyl(1S)-1-{[methoxy(methyl)amino]carbonyl}pentylcarbamate in 100 mL oftoluene over 30 min. After stirring at −20° C. for 2 h, 300 mL of 3Maqueous sodium chloride was added dropwise, and the layers wereseparated. The toluene portion was washed with 100 mL of 1 Nhydrochloric acid (2×), 50 mL of 0.1 N sodium hydroxide (2×), 50 mL ofbrine, dried over anhydrous magnesium sulfate, and then concentrated to200 mL. The aldehyde solution was used immediately. An aliquot wasremoved and concentrated, and the aldehyde was analyzed immediately.¹H-NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 7.23 (d, J=7 Hz, 1H), 3.75(m, 1H), 1.70-1.08 (m, 6H), 1.36 (s, 9H), 0.81 (t, J=6 Hz, 3H).

Example 3c Preparation of tert-butyl(1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl(1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate

To a solution of 12.4 g (58 mmol) of tert-butyl(1S)-1-formylpentylcarbamate in 135 mL of methanol was added 3.77 g (58mmol) of potassium cyanide followed by 3.32 mL (58 mmol) of acetic acid.The reaction mixture was stirred for 16 h and concentrated under reducedpressure to afford 14.2 g of an oil. The oil was dissolved in 140 mL ofacetic acid, and 1.4 g of platinum oxide on carbon was added. Thereaction mixture was hydrogenated under 50 psi hydrogen gas for 4 h, andfiltered through a celite plug. The filtrate was concentrated, and theresidue dissolved in ethyl acetate. The ethyl acetate solution waswashed with 1M sodium hydroxide and brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with 2M ammonia inmethanol:ethyl acetate (2.5:7.5) to afford 6.61 g (46%) of tert-butyl(1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl(1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate. ¹H-NMR (300 MHz,diastereomers, DMSO-d₆): δ 6.55 and 6.21 ((d, J=9 Hz), (d, J=9 Hz), 1H),3.55-3.09 (m, 4H), 1.39-1.05 (m, 15H), 0.87 (m, 3H); ES-LCMS m/z 247(M+H).

Example 3d Preparation of tert-butyl(1S)-1-{(1SR)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& tert-butyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate

To a biphasic mixture of 4.93 g (20 mmol) of tert-butyl(1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl(1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate in 32 mLdichloromethane and 15 mL saturated sodium bicarbonate was added 24 mL(24 mmol) of 1 M 2-pyridinesulfonyl chloride in dichloromethane. Thereaction mixture was stirred overnight and then extracted withdichloromethane. The extract was washed with brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with ethylacetate:hexanes (6:4) to afford 5.00 g (65%) of tert-butyl(1S)-1-{(1SR)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& tert-butyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate.¹H-NMR (300 MHz, DMSO-d₆): δ 8.73 (d, J=4 Hz, 1H), 8.09 (t, J=8 Hz, 1H),7.93 (dd, J=8 Hz, J=4 Hz, 1H), 7.68 (m, 1H), 7.60 and 7.54 ((t, J=6 Hz),(t, J=6 Hz), 1H), 6.55 and 6.36 ((d, J=9 Hz), (d, J=9 Hz), 1H), 4.78 (m,1H), 3.50-2.70 (m, 4H), 1.61 (m, 1H), 1.37-1.05 (m, 14H), 0.86 (t, J=7Hz, 3H); ES-LCMS m/z 410 (M+Na).

Example 3e Preparation ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamideHydrochloride

To a solution of 5.0 g (13 mmol) of tert-butyl(1S)-1-{(1SR)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& tert-butyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamatein 15 mL of dioxane was added 20 mL of 4M hydrochloric acid in dioxane.The reaction mixture was stirred for 2 h and concentrated under reducedpressure to leave 4.2 g (>99) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamidehydrochloride. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.10-7.92 (m,5H), 7.79-7.65 (m, 2H), 3.86 (s, 1H), 3.16-2.91 (m 3H), 1.58-1.33 (m,2H), 1.20 (m, 4H), 0.84 (m, 3H); ES-LCMS m/z 288 (M+H).

Example 3f Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate

To a solution of 90 mg (0.21 mmol) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamidehydrochloride and 83 mg (0.63 mmol) of N,N-diisopropylethylamine in 2 mLN,N-dimethylformamide was added 102 mg (0.21 mmol) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl4-nitrophenyl carbonate. The reaction mixture was stirred at roomtemperature for 48 h. It was diluted with ethyl acetate, washed with oneportion of 1M sodium hydroxide and with 1 portion of brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel chromatography eluting with ethylacetate:hexanes (3:1) to afford 90 mg (68%) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate.¹H-NMR (300 MHz, DMSO-d₆): δ 8.70 (d, J=4 Hz, 1H), 8.11-7.45 (m, 10H),6.76 (s, 1H), 6.54 (d, J=9 Hz, 1H), 4.90-4.76 (m, 2H), 4.46 (d, J=13 Hz,1H), 4.16 (m, 1H), 3.05 (m, 1H), 1.27 (m, 1H), 1.05-0.86 (m, 14H), 0.68(m, 3H); ES-LCMS m/z 648 (M+Na).

Example 3g Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To a solution of 90 mg (0.14 mmol) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamatein 2 mL of dichloromethane was added 76 mg (0.18 mmol) of Dess-Martinperiodinane. The reaction mixture was stirred for 15 min, and thenfiltered through a celite plug with dichloromethane. The filtrate wasconcentrated, and the residue was purified by silica gel chromatographyeluting with ethyl acetate:hexanes (6.5:3.5) to afford 56 mg (62%) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. ¹H-NMR (300MHz, T=100° C., DMSO₆): δ 8.66 (d, J=4 Hz, 1H), 8.08-7.60 (m, 9H), 7.17(m, 1H), 6.72 (d, J=2 Hz, 1H), 4.90 (d, J=9 Hz, 1H), 4.49 (d, J=14 Hz,1H), 4.26-3.85 (m, 4H), 1.56 (m, 1H), 1.40 (m, 1H), 1.29-1.01 (m, 13H)0.78 (m, 3H); ES-LCMS m/z 646 (M+Na); HRMS C₂₉H₃₆F₃N₅O₅S₁ m/z 646.2287(M+Na)⁺Cal; 646.2283 (M+Na)⁺.

Example 4 Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(4-morpholinylcarbonyl)amino]acetyl}pentylcarbamate

Example 4a Preparation of tert-butyl(1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate& tert-butyl(1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate

To a solution of 100 mg (0.41 mmol) of tert-butyl(1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl(1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate and 0.070 mL (0.41mmol) of N,N-diisopropylethylamine in 2 mL dichloromethane was added0.050 mL (0.41 mmol) 4-morpholinecarbonyl chloride. The reaction mixturewas stirred at room temperature for 18 h, diluted with dichloromethane,and washed with 1N hydrochloric acid and brine. After drying overanhydrous magnesium sulfate, the solution was concentrated under reducedpressure, and the residue was purified by silica gel chromatographyeluting with ethyl acetate to afford 130 mg (89%) of tert-butyl(1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate& tert-butyl(1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate.¹H-NMR (300 MHz, DMSO-d₆): δ 6.55-6.36 (m, 2H), 5.00-4.65 (m, 1H),3.60-3.23 (m, 9H), 3.10-2.80 (m, 2H), 1.40-1.05 (m, 15 H), 0.87 (m, 1H);ES-LCMS m/z 382 (M+Na).

Example 4b Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate

To a solution of 130 mg (0.36 mmol) of tert-butyl(1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate& tert-butyl(1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamatein 1 mL of dioxane was added 5 mL of 4M hydrochloric acid in dioxane.The reaction mixture was stirred for 2 h and concentrated under reducedpressure. Half of the product was carried forward. This material wasslurried in N,N-dimethylformamide before 0.094 mL (0.54 mmol) ofN,N-diisopropylethylamine was added, followed by 86 mg (0.18 mmol) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl4-nitrophenyl carbonate. The reaction mixture was stirred at roomtemperature for 18 h, and then diluted with ethyl acetate before beingwashed with 1M sodium hydroxide and brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with ethyl acetate toafford 60 mg (55%) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate.¹H-NMR (300 MHz, DMSO-d₆): δ 7.99 (m, 2H), 7.74 (d, J=8 Hz, 2H), 6.77(s, 1H), 6.58 (d, J=9 Hz, 1H), 6.33 (m, 1H), 4.95-4.75 (m, 2H), 4.48 (d,J=13 Hz, 1H), 4.19 (t, J=12 Hz, 1H), 3.45-3.10 (m, 13H), 1.25 (m, 1H),0.99 (m, 14H), 0.67 (m, 3H); ES-LCMS m/z 620 (M+Na).

Example 4c Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(4-morpholinylcarbonyl)amino]acetyl}pentylcarbamate

(1S)-2,2-Dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(4-morpholinylcarbonyl)amino]acetyl}pentylcarbamate wasprepared (50% yield) as in example 3g except that(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate &(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamatewere substituted for(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate.¹H-NMR (300 MHz, DMSO-d₆): δ 8.00 (d, J=8 Hz, 2H), 7.74 (m, 3H), 7.47(d, J=8 Hz, 1H), 6.81-6.72 (m, 2H), 4.87 (d, J=9 Hz, 1H), 4.48 (m, 1H),4.22 (m, 1H), 3.88-3.75 (m, 2H), 3.53 (t, J=4 Hz, 4H), 3.38 under waterpeak (m, 1H), 3.24 (t, J=4 Hz, 4H), 1.55 (m, 1H), 1.33 (m, 1H),1.15-0.85 (m, 13H), 0.72 (t, J=6 Hz, 3H); ES-LCMS m/z 596 (M+H); HRMSC₂₉H₄₀N₅O₅F₃ m/Z 596.3060 (M+H)⁺Cal; 596.3047 (M+H)⁺.

Example 5 Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(6-fluoro-2-pyridinyl)amino]acetyl}pentylcarbamate

Example 5a Preparation of tert-butyl(1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate& tert-butyl(1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate

To a solution of 100 mg (0.41 mmol) of tert-butyl(1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl(1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate and 0.07 mL (0.46mmol) of N,N-diisopropylethylamine in 0.5 mL dioxane was added 0.042 mL(0.46 mmol) of 2,6-difluoropyridine. The reaction mixture was stirred at45° C. for 16 h, then at 50° C. for 20 h. The reaction mixture was thenallowed to cool before being diluted with ethyl acetate, washed withbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with ethyl acetate:hexanes (3:7) to afford 40 mg (29%) oftert-butyl(1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate& tert-butyl(1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate.ES-LCMS m/z 364 (M+Na).

Example 5b Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate

To a solution of 40 mg (0.12 mmol) of tert-butyl(1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate& tert-butyl(1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamatein 1 mL dioxane was added 5 mL of 4M hydrochloric acid in dioxane. Thereaction mixture was stirred for 2 h before being concentrated underreduced pressure. The residue was dissolved in 1 mL ofN,N-dimethylformamide before 0.081 mL (0.47 mmol) ofN,N-diisopropylethylamine and 56 mg (0.12 mmol) of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl4-nitrophenyl carbonate were added. The reaction mixture was stirred atroom temperature for 18 h, diluted with ethyl acetate, washed with 1Msodium hydroxide and brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with ethyl acetate:hexanes (2:3) to afford 40mg (59%) of(1S)-2,2-dimethyl-1-({3-[4(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate.ES-LCMS m/z 602 (M+Na).

Example 5c Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(6-fluoro-2-pyridinyl)amino]acetyl}pentylcarbamate

(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(6-fluoro-2-pyridinyl)amino]acetyl}pentylcarbamate was preparedas in example 3g (15% yield) except that(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamatewere substituted for(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate.ES-LCMS m/z 600 (M+Na); HRMS C₂₉H₃₅N₅O₃F₄ m/z 578.2754 (M+H)⁺Cal;578.2745 (M+H)⁺.

Example 6 Preparation of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 6a Preparation of (2S)-3,3-dimethyl-1,2,4-butanetriol

To a 0° C. solution of 5.01 g (38.5 mmol) of (S)-(+)-pantolactone in 150mL of methanol was added 3.72 g (98.5 mmol) of sodium borohydridecarefully. After gas evolution had subsided, the ice-bath was removedand the reaction mixture was closely monitored, cooling again to 0° C.with an ice-water bath as needed when gas evolution became vigorous. Theice-water bath was removed and the reaction mixture was stirred at roomtemperature for 4 h. Dowex 50Wx4-400 (H⁺) resin was added to thesolution until the reaction mixture was neutral. The resin was filteredoff and the filtrate was concentrated under reduced pressure. The oilwas diluted and concentrated with portions of methanol and then toluene.The remaining clear oil was dried under high vacuum to afford 5.16 g(>99%) of (2S)-3,3-dimethyl-1,2,4-butanetriol. ¹H-NMR (300 MHz, CDCl₃):δ 3.82-3.49 (m, 5H), 3.11 (d, J=4 Hz, 1H), 2.62 (m, 1H), 2.42 (m, 1H),0.98 (d, J=6 Hz, 6H).

Example 6b Preparation of(2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butylMethanesulfonate

To a 0° C. solution of 25.3 g (189 mmol) of(2S)-3,3-dimethyl-1,2,4-butanetriol in 170 mL of pyridine was addeddropwise 29.1 mL (378 mmol) of methanesulfonyl chloride. The reactionmixture was allowed to warm slowly to room temperature, and was stirredfor 18 h. It was then diluted with dichloromethane. To the resultingsolution was added 200 mL of 1 N hydrochloric acid, followed by enoughconcentrated hydrochloric acid to acidify the aqueous phase (pH=2). Themixture was extracted with dichloromethane, and the combined extractswere washed with brine and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting withacetone:dichloromethane (1:9) to afford 21.75 g (52%) of(2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butylmethanesulfonate. ¹H-NMR (300 MHz, DMSO-d₆): δ 5.48 (d, J=6 Hz, 1H),4.30 (dd, J=3 Hz, J=10 Hz, 1H), 4.05-3.91 (m, 3H), 3.16 (d, J=4 Hz, 6H),0.90 (d, J=13 Hz, 6H).

Example 6c Preparation of (3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol

A solution of 21.7 g (75 mmol) of(2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butylmethanesulfonate and 24.4 mL (228 mmol) of benzylamine in 200 mL ofethanol was heated to 120° C. for 18 h in a sealed pressure reactor. Thereaction mixture was allowed to cool to room temperature before thereactor was vented and the reaction mixture was concentrated underreduced pressure to afford 100 mL of solution. The solution was dilutedwith 50 mL water and acidified with concentrated hydrochloric acid. Theaqueous phase was washed with ether, basicified with 5M sodiumhydroxide, and extracted with ether. The ether extract was concentratedunder reduced pressure and the residue was purified by silica gelchromatography eluting with 2M ammonia in methanol:ethyl acetate(0.25:9.75) to afford 13.8 g (90%) of(3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol. ¹H-NMR (300 MHz, CDCl₃): δ7.36-7.30 (m, 5H), 3.77 (br s, 1H), 3.65 (s, 2H), 2.99-2.93 (m, 1H),2.64-2.55 (m, 2H), 2.31 (d, J=9 Hz, 1H), 1.76 (d, J=7 Hz, 1H), 1.09 (d,J=1 Hz, 6H).

Example 6d Preparation of (3S)-4,4-dimethyl-3-pyrrolidinol Hydrochloride

To a solution of 6.34 g (41.7 mmol) of(3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol in 250 mL of ethanol and 50 mLof 1N hydrochloric acid was added 300 mg of 10% palladium on carbon. Thereaction mixture was stirred under 40 psi of hydrogen gas for 18 h. Tothe reaction mixture was added 300 mg of 10% palladium on carbon and 2mL of concentrated hydrochloric acid. The reaction mixture was stirredunder 40 psi of hydrogen gas for 72 h. The catalyst was filtered offover celite, and the filtrate was concentrated. Several portions oftoluene were distilled from the residue, which was then dried under highvacuum to afford 4.74 g (>99%) of (3S)-4,4-dimethyl-3-pyrrolidinolhydrochloride. ¹H-NMR (300 MHz, DMSO-d₆): δ 9.46 (d, J=40 Hz, 2H), 5.43(br s, 1H), 3.75 (m, 1H), 3.36 (m, 1H), 2.88 (m, 3H), 0.96 (d, J=10 Hz,6H).

Example 6e Preparation of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethyl-3-pyrrolidinol

To a slurry of 600 mg (4 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinolhydrochloride and 670 mg (4 mmol) of 2-chlorobenzthiazole was added asolution of 1.0 g (12 mmol) of sodium bicarbonate in water. The reactionmixture was heated to 80° C. and stirred overnight. It was then dilutedwith water, the resulting mixture was extracted with ethyl acetate. Theextracts were combined, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to afford 950 mg (96%) of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethyl-3-pyrrolidinol. ¹H-NMR (300MHz, DMSO-₆): δ 7.76 (d, J=8 Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.27 (t, J=8Hz, 1H), 7.04 (t, J=8 Hz, 1H), 5.27 (d, J=5 Hz, 1H), 3.84-3.77 (m, 2H),3.39-3.25 under DMSO peak (m, 3H), 1.05 (d, J=8 Hz, 6H); ES-LCMS m/z 249(M+H).

Example 6f Preparation of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl 4-nitrophenylCarbonate

To a solution of 950 mg (3.83 mmol) of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethyl-3-pyrrolidinol in 10 mL ofdichloromethane was added 920 mg (4.6 mmol) of 4-nitrophenylchloroformate followed by the dropwise addition of 0.37 mL (4.6 mmol) ofpyridine. The reaction mixture was stirred at room temperature for 18 h.It was then diluted with ethyl acetate, washed with saturated sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with ethyl acetate:hexanes (3.5:6.5) toafford 1.17 g (74%) of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl 4-nitrophenylcarbonate. ¹H-NMR (300 MHz, DMSO-d₆): δ 8.35 (d, J=9 Hz, 2H), 7.81 (d,J=8 Hz, 1H), 7.64 (d, J=9 Hz, 2H), 7.50 (d, J=8 Hz, 1H), 7.31 (t, J=8Hz, 1H), 7.09 (t, J=8 Hz, 1H), 5.06 (d, J=4 Hz, 1H), 4.13 (dd, J=13 Hz,J=5 Hz, 1H), 3.86 (d, J=4 Hz, 1H), 3.53-3.41 under DMSO peak (m, 2H),1.24 (s, 3H), 1.18 (s, 3H); ES-LCMS m/z 414 (M+H).

Example 6g Preparation of(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate

(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamatewere prepared as in example 3f except that(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl 4-nitrophenylcarbonate was substituted for(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl4-nitrophenyl carbonate. 83% yield. ES-LCMS m/z 562 (M+H).

Example 6h Preparation of(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

(1S)-2,2-Dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate was preparedas in example 3g (27% yield) except that(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamatewere substituted for(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate.¹H-NMR (300 MHz, DMSO-d₆): δ 8.67 (d, J=6 Hz, 1H), 8.13-8.03 (m, 2H),7.88 (d, J=8 Hz, 1H), 7.77 (d, J=8 Hz, 2H), 7.65 (dd, J=7 Hz, J=5 Hz,1H), 7.45 (d, J=8 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.04 (t, J=8 Hz, 1H),4.89 (d, J=4 Hz, 1H), 4.15-3.95 (m, 5H), 3.53-3.40 under DMSO peak (m,2H), 1.60 (m, 1H), 1.42 (m, 1H), 1.23 (m, 4H), 1.09 (s, 3H), 1.06 (s,3H), 0.82 (m, 3H); ES-LCMS m/z 560 (M+H); HRMS C₂₆H₃₃N₅O₅S₂ m/z 560.2001(M+Na)⁺Cal; 560.2010 (M+Na)⁺.

Example 7 Preparation of(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 7a Preparation of (4S)-4-tert-butyl-1,3,2-dioxathiolane2,2-dioxide

To 5.63 g (47.63 mmol) of (2S)-3,3-dimethyl-1,2-butanediol in 48 mL ofcarbon tetrachloride was added 3.47 mL (47.63 mmol) of thionyl chloride.The resulting mixture was heated at reflux for 1 h, and cooled to 0° C.,before 48 mL of acetonitrile was added. Then, 1.0 mg (4.8 μmol) ofruthenium(III) chloride hydrate was added, followed by 15.28 g (71.45mmol) of sodium periodate. The reaction mixture was diluted with 71 mLof water and stirred for 2 h. It was then extracted with diethyl ether.The extract was washed with saturated aqueous sodium bicarbonate, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by silica gel column chromatography eluting with anethyl acetate:hexanes solution (3:7) to give 8.33 g (97%) of(4S)-4-tert-butyl-1,3,2-dioxathiolane 2,2-dioxide. R_(f)=0.30 (3:7 ethylacetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆): δ 4.99-4.88 (m, 2H), 4.78(t, J=8 Hz, 1H), 0.94 (s, 9H).

Example 7b Preparation of(2S)-3,3-dimethyl-1-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-butanol

To 999.9 mg (5.55 mmol) of (4S)-4-tert-butyl-1,3,2-dioxathiolane2,2-dioxide in 18 mL of N,N-dimethylformamide was added 755.0 mg (5.55mmol) of 3-(trifluoromethyl)-1H-pyrazole. Then, 805.2 mg (5.83 mmol) ofpotassium carbonate was added, and the mixture was heated at 100° C. for22 h. The resulting solution was cooled and 20 mL of acetylchloride:methanol (1:9) were added. The reaction mixture was stirred for2 h, and then saturated aqueous sodium bicarbonate was added. Themixture was extracted with ethyl acetate, and the extract was dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by silica gel column chromatography eluting with an ethylacetate:hexanes solution (1:4) to give 736.5 mg (56%) of(2S)-3,3-dimethyl-1-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-butanol anda small amount of the other regioisomer. R_(f)=0.23 (1:4 ethylacetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆): δ 7.90 (s, 1H), 6.65 (d,J=2 Hz, 1H), 4.93 (br s, 1H), 4.30 (dd, J=14 Hz, J=2 Hz, 1H), 3.96 (dd,J=14 Hz, 10 Hz, 1H), 3.45 (d, J=10 Hz, 1H), 0.90 (s, 9H); ES-LCMS m/z237 (M+H).

Example 7c Preparation of 4-nitrophenyl(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propylCarbonate

To 875.3 mg (3.71 mmol) of(2S)-3,3-dimethyl-1-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-butanol in12 mL of 1,2-dichloroethane at room temperature was added 746.8 g (3.71mmol) of 4-nitrophenyl chloroformate. Then, 359.6 μL (4.45 mmol) ofpyridine was added and the solution was heated at reflux for 22 h. Uponcooling to room temperature, saturated aqueous sodium bicarbonate wasadded to the solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by silica gel column chromatography eluting with anethyl acetate:hexanes solution (1:4) to give 1.39 g (93%) of4-nitrophenyl(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propylcarbonate. R_(f)=0.29 (3:7 ethyl acetate:hexanes); ¹H-NMR (300 MHz,DMSO-d₆): δ 8.28 (d, J=9 Hz, 2H), 8.07 (s, 1H), 7.31 (d, J=9 Hz, 2H),6.74 (s, 1H), 4.87 (d, J=8 Hz, 1H), 4.69 (d, J=14 Hz, 1H), 4.42 (dd,J=15 Hz, J=10 Hz, 1H), 1.03 (s, 9H); ES-LCMS m/z 424 (M+H).

Example 7d Preparation of(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To 102.6 mg (314.3 μmol) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamidehydrochloride at room temperature was added 105.7 mg (105.7 μmol) of4-nitrophenyl(1S)-2,2dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propylcarbonate in 2.6 mL of dimethylformamide. This was followed by theaddition of 183.5 μL (1.05 mmol) of N,N-diisopropylethylamine. Themixture was stirred for 16 h at room temperature. It was concentrated,and saturated sodium bicarbonate was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography eluting with an ethyl acetate:hexanes solution(7:3) to give 90.8 mg (63%) of a mixture of alcohols. The alcoholmixture was dissolved in 3.3 mL of dichloromethane at room temperature,and 87.6 mg (206.5 μmol) of Dess-Martin periodinane was added, and thereaction mixture was stirred for 60 min. It was then poured intosaturated sodium metabisulfite, and the resulting mixture wassubsequently neutralized with saturated sodium bicarbonate. It was thenextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby silica gel column chromatography eluting with an ethylacetate:hexanes solution (3:2) to give 61.7 mg (68%) of(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. R_(f)=0.28(3:2 ethyl acetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆, Temp=110° C.): δ8.63 (d, J=4 Hz, 1H), 8.20 (s, 1H), 8.02 (t, J=8 Hz, 1H), 7.86 (d, J=8Hz, 1H), 7.77 (s, 1H), 7.60 (dd, J=7 Hz, J=5 Hz, 1H), 7.07 (br s, 1H),6.53 (s, 1H), 4.82 (d, J=10 Hz, 1H), 4.47 (d, J=14 Hz, 1H), 4.22 (dd,J=14 Hz, J=10 Hz, 1H), 4.14-3.88 (m, 3H), 1.68-1.52 (m, 1H), 1.50-1.34(m, 1H), 1.36-1.10 (m, 4H), 0.96 (s, 9H), 0.84 (t, J=7 Hz, 3H); HRMSC₂₃H₃₃F₃N₅O₅S m/z 548.2155 (M+H)_(cal); 548.2146 (M+H)_(obs).

Example 8 Preparation of(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To 178.2 mg (560.0 μmol) ofN-[(2S,3S)-3-amino-2-hydroxybutyl]-2-pyridinesulfonamide hydrochloride &N-[(2R,3S)-3-amino-2-hydroxybutyl]-2-pyridinesulfonamide hydrochlorideat room temperature was added 244.8 mg (560.0 μmol) of 4-nitrophenyl(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propylcarbonate in 5.6 mL of dimethylformamide. This was followed by theaddition of 390.2 μL (2.24 mmol) of N,N-diisopropylethylamine, and thereaction mixture was stirred for 44 h at room temperature. The solutionwas concentrated, saturated sodium bicarbonate was added, and theresulting mixture was extracted with ethyl acetate. The extract waswashed with saturated sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by silicagel column chromatography eluting with an ethyl acetate:hexanes solution(4:1) to give 250.2 mg (88%) of a mixture of alcohols. The alcohols weredissolved in 4.9 mL of chloroform at room temperature, 261.4 mg (616.2μmol) of Dess-Martin periodinane was added, and the reaction mixture wasstirred for 45 min. The reaction mixture was poured into saturatedsodium metabisulfite. This mixture was subsequently neutralized withsaturated sodium bicarbonate, and extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by silica gel columnchromatography eluting with an ethyl acetate:hexanes solution (7:3) togive 164.0 mg (66%) of(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate.R_(f)=0.32 (7:3 ethyl acetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆,Temp=110° C.): δ 8.64 (d, J=5 Hz, 1H), 8.02 (t, J=8 Hz, 1H), 7.87 (d,J=8 Hz, 1H), 7.79 (s, 1H), 7.68-7.58 (m, 1H), 7.60 (dd, J=8 Hz, J=5 Hz,1H), 7.18-7.04 (m, 1H), 6.57 (s, 1H), 4.79 (d, J=8 Hz, 1H), 4.48 (d,J=14 Hz, 1H), 4.21 (dd, J=14 Hz, J=9 Hz, 1H), 4.15-3.98 (m, 3H), 1.12(d, J=7 Hz, 3H), 0.95 (s, 9H); HRMS C₂₀H₂₇F₃N₅O₅S m/z 506.1685(M+H)_(Cal); 506.1680 (M+H)_(Obs).

Example 9 Preparation of(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 9a Preparation of 5-(trifluoromethyl)-1, 3-benzothiazole

A mixture of 5.1 g (22.2 mmol) of 2-amino-4-(trifluoromethyl)benzenethiol hydrochloride, 5.5 mL (33.3 mmol) of triethylorthoformate,and 2 drops of sulfuric acid was slowly heated to 180° C. over 1 h. Theethanol formed was allowed to escape via a short path distillationstill. The reaction mixture was cooled to room temperature and theresidue was dissolved in ethyl acetate, washed with saturated sodiumbicarbonate, dried over anhydrous magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel chromatography with ethylacetate:hexane (1:9) to afford 3.8 g (86%) of5-(trifluoromethyl)-1,3-benzothiazole as a solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 9.58 (s, 1H), 8.44-8.42 (m, 2H), 7.80 (d, 1H).

Example 9b Preparation of2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]-1-propanol

To a stirred solution of 3.8 g (19.0 mmol) of5-(trifluoromethyl)-1,3-benzothiazole in 30 mL of tetrahydrofuran at−78° C. was added 13.1 mL (21.0 mmol) of a 1.6 M solution ofn-butyllithium in hexane over 45 min. Then, 1.8 g (21.0 mmol) oftrimethylacetaldehyde in 10 mL of tetrahydrofuran was added dropwiseover 30 min. The reaction mixture was stirred for 1 h at −78° C., andthen allowed to warm to 0° C. Then, 25 mL of water was added and themixture was extracted with 80 mL of ether. The ether was washed with 40mL of water (3×), dried over anhydrous magnesium sulfate, andconcentrated in vacuo. The residue was purified by silica gelchromatography eluting with ethyl acetate:hexane (1:9) to afford 1.8 g(33%) of2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]-1-propanol asan off-white solid. The enantiomers were separated in 98.8% ee using aChiralpak AD, 10 micron column with a mobile phase of 90% carbondioxide: 10% methanol and a flow rate of 2.0 mL/minute. ¹H-NMR (400MHz,DMSO-d₆): δ 8.33-8.29 (m, 2H), 7.71 (d, J=8 Hz, 1H), 6.61 (d, J=5 Hz,1H), 4.60 (d, J=5 Hz, 1H), 0.97 (s, 9H).

Example 9c Preparation of(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl4-nitrophenyl Carbonate

A solution of 715 mg (2.5 mmol) of(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]-1-propanoland 0.40 mL (4.9 mmol) of pyridine in 25 mL of dichloromethane wascooled to 5° C. Then, 755 mg (3.7 mmol) of 4-nitrophenylchloroformatewas added and the reaction mixture was allowed to warm to ambienttemperature. After being stirred for 48 h, the reaction mixture wasconcentrated in vacuo. The residue was taken up in 80 mL of ethylacetate, and this solution was washed with 40 mL of water (2×), driedover anhydrous magnesium sulfate, and concentrated. The residue waspurified by silica gel chromatography eluting ethyl acetate:hexane (1:9)to afford 835 mg (74%) of(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl4-nitrophenyl carbonate as a white foam. ¹H-NMR (400 MHz, DMSO₆): δ8.44-8.40 (m, 2H), 8.29 (d, J=7 Hz, 2H), 7.82 (d, J=8 Hz, 1H), 7.57 (d,J=7 Hz, 2H), 5.85 (s, 1H), 1.08 (s, 9H).

Example 9d Preparation of(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To 100.9 mg (280.0 μmol) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamidehydrochloride at room temperature was added 127.3 mg (280.0 μmol) of4-nitrophenyl(1S)-2,2-dimethyl-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propylcarbonate in 2.8 mL of dimethylformamide. This was followed by theaddition of 195.1 μL (1.12 mmol) of N,N-diisopropylethylamine, and thereaction mixture was stirred for 14 h at room temperature. The solutionwas concentrated, saturated sodium bicarbonate was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography eluting with an ethyl acetate:hexanes solution(7:3) to give 136.9 mg (81%) of a mixture of alcohols. The alcohols weredissolved in 4.5 mL of dichloromethane at room temperature, and 120.4 mg(283.9 μmol) of Dess-Martin periodinane was added. The reaction mixturewas stirred for 60 min before being poured into saturated sodiummetabisulfite. The resulting mixture was then neutralized with saturatedsodium bicarbonate, before being extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by silica gel columnchromatography eluting with an ethyl acetate:hexanes solution (1:1) togive 71.7 mg (53%) of(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. R_(f)=0.29(1:1 ethyl acetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆, Temp=110° C.): δ8.63 (d, J=4 Hz, 1H), 8.31 (s, 1H), 8.30 (d, J=7 Hz, 1H), 8.20 (s, 1H),8.02 (t, J=8 Hz, 1H), 7.87 (d, J=8 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 7.68(br s, 1H), 7.59 (dd, J=7 Hz, J=5 Hz, 1H), 5.67 (s, 1H), 4.22-4.02 (m,3H), 1.78-1.64 (m, 1H), 1.64-1.44 (m, 1H), 1.36-1.22 (m, 4H), 1.07 (s,9H), 0.82 (t, J=6 Hz, 3H); HRMS C₂₆H₃₂F₃N₄O₅S₂ m/z 601.1766 (M+H)_(Cal);601.1759 (M+H)_(Obs).

Example 10 Preparation of(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To 76.6 mg (240.6 μmol) ofN-[(2S,3S)-3-amino-2-hydroxybutyl]-2-pyridinesulfonamide hydrochloride &N-[(2R,3S)-3-amino-2-hydroxybutyl]-2-pyridinesulfonamide hydrochloridein 2.0 mL of dimethylformamide at room temperature was added 99.4 mg(218.7 μmol) of 4-nitrophenyl(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propylcarbonate in 2.4 mL of dimethylformamide. This was followed by theaddition of 152.4 μL (874.9 mmol) of N,N-diisopropylethylamine and themixture was stirred for 17 h at room temperature. The solution wasconcentrated, saturated sodium bicarbonate was added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography eluting with an ethyl acetate:hexanes solution(7:3) to give 114.5 mg (93%) of a mixture of alcohols. The alcohols weredissolved in 5.1 mL of dichloromethane at room temperature and 108.3 mg(255.3 μmol) of Dess-Martin periodinane was added. The reaction mixturewas stirred for 60 min, and then poured into saturated sodiummetabisulfite. The resulting mixture was neutralized with saturatedsodium bicarbonate, and then extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by silica gel columnchromatography eluting with an ethyl acetate:hexanes solution (3:2) togive 81.3 mg (71%) of(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate.R_(f)=0.21 (3:2 ethyl acetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆,Temp=110° C.): δ 8.63 (d, J=5 Hz, 1H), 8.31 (s, 1H), 8.30 (d, J=8 Hz,1H), 8.21 (s, 1H), 8.03 (t, J=8 Hz, 1H), 7.88 (d, J=8 Hz, 1H), 7.73 (d,J=9 Hz, 1H), 7.71 (br s, 1H), 7.59 (dd, J=7 Hz, J=5 Hz, 1H), 5.67 (s,1H), 4.26-4.02 (m, 3H), 1.24 (t, J=7 Hz, 3H), 1.07 (s, 9H); HRMSC₂₃H₂₆F₃N₄O₅S₂ m/z 559.1297 (M+H)_(cal); 559.1285 (M+H)_(Obs).

Example 11 Preparation of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 11a Preparation of 4-[4-(trifluoro)phenyl]-1H-pyrazole

To 13.70 mL (146.95 mmol) of phosphorus oxychloride at 0° C. was added13.92 mL (179.77 mmol) of anhydrous N,N-dimethylformamide dropwise. Theresulting solution was stirred for 15 min at room temperature. Then,10.00 g (48.98 mmol) of [4-(trifluoromethyl)phenyl]acetic acid in 24 mLof anhydrous N,N-dimethylformamide was added dropwise. The resultingmixture was stirred for 19 h at 70° C., and then poured onto ice.Following neutralization with potassium carbonate, 30 g of sodiumhydroxide was added, and the resulting solution was heated at 50° C. for15 min. It was then cooled to 0° C. and filtered. The filter cake waswashed with water and dried under a vacuum to give3-(dimethylamino)-2-[4-(trifluoromethyl)phenyl]-2-propenal. This drysolid was dissolved in 122 mL of methanol, 3.07 mL (97.97 mmol) ofhydrazine was added, and the solution was stirred for 6 h at roomtemperature. It was poured into water, and the resulting mixture wasfiltered. The filter cake was washed with water, followed by hexanes,and dried under vacuum to give 8.35 g (80% yield) of4-[4-(trifluoro)phenyl]-1H-pyrazole. R_(f)=0.26 (1:19methanol:dichloromethane); ¹H-NMR (300 MHz, DMSO-d₆): δ 13.09 (br s,1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.82 (d, J=8 Hz, 2H), 7.68 (d, J=8 Hz,2H); ES-LCMS m/z 213 (M+H).

Example 11b Preparation of(2S)-3,3-dimethyl-1-{4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol

To 2.00 g (19.97 mmol) of (S)-3,3-dimethyl-1,2-epoxybutane in 5.0 mL ofethanol was added 5.08 g (23.96 mmol) of4-[4-(trifluoro)phenyl]-1H-pyrazole. Then, 3.90 mL (27.96 mmol) oftriethylamine was added, and the solution was stirred in a sealed tubeat 85° C. for 16 h. It was cooled and concentrated, and the residue waspurified by silica gel column chromatography eluting with an ethylacetate:hexanes solution (3:7) to give 3.30 g (53%) of(2S)-3,3-dimethyl-1-{4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol.R_(f)=0.31 (3:7 ethyl acetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆): δ8.29 (s, 1H), 7.99 (s, 1H), 7.78 (d, J=8 Hz, 2H), 7.68 (d, J=8 Hz, 2H),4.93 (d, J=6 Hz, 1H), 4.26 (dd, J=14 Hz, J=2 Hz, 1H), 3.89 (dd, J=14 Hz,J=10 Hz, 1H), 3.49 (dd, J=8 Hz, J=6=Hz, 1H), 0.91 (s, 9H); ES-LCMS m/z313 (M+H).

Example 11c Preparation of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl4-nitrophenyl Carbonate

To 3.30 g (10.57 mmol) of(2S)-3,3-dimethyl-1-{4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanolin 200 mL of tetrahydrofuran at 0° C. was added 7.26 mL (11.62 mmol) of1.6 M n-butyllithium in hexanes, and the resulting solution was stirredfor 10 min. Then, 3.19 g (15.84 mmol) of 4-nitrophenyl chloroformate in11 mL of tetrahydrofuran was added, and the solution was stirred at roomtemperature for 75 min. Saturated aqueous sodium bicarbonate was added,and the resulting mixture was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby silica gel column chromatography eluting with an ethylacetate:hexanes solution (3:7) to give 3.92 g (78%) of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl4-nitrophenyl carbonate. R_(f)=0.19 (3:7 ethyl acetate:hexanes); ¹H-NMR(300 MHz, DMSO-d₆): δ 8.44 (s, 1H), 8.14 (d, J=9 Hz, 2H), 8.08 (s, 1H),7.79 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 2H), 7.27 (d, J=9 Hz, 2H), 4.88(dd, J=10 Hz, J=2 Hz, 1H), 4.61 (d, J=13 Hz, 1H), 4.32 (dd, J=15 Hz,J=10 Hz, 1H), 1.05 (s, 9H); ES-LCMS m/z 478 (M+H).

Example 11d Preparation of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To 103.2 mg (286.7 μmol) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamidehydrochloride at room temperature was added 124.4 mg (260.6 μmol) of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl4-nitrophenyl carbonate in 2.6 mL of dimethylformamide. This wasfollowed by the addition of 181.5 μL (1.04 mmol) ofN,N-diisopropylethylamine, and the reaction mixture was stirred for 16 hat room temperature. It was then concentrated, saturated sodiumbicarbonate was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by silica gel column chromatography eluting with an ethylacetate:hexanes solution (4:1) to give 111.9 mg (69%) of a mixture ofalcohols. The alcohols were dissolved in 3.6 mL of dichloromethane atroom temperature, 94.8 mg (223.6 mmol) of Dess-Martin periodinane wasadded, and the reaction mixture was stirred for 120 min. It was pouredinto saturated sodium metabisulfite, and the resulting mixture wasneutralized with saturated sodium bicarbonate and extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography eluting with an ethyl acetate:hexanes solution(7:3) to give 75.3 mg (68%) of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. R_(f)=0.27(7:3 ethyl acetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆, Temp=110° C.): δ8.62 (d, J=4 Hz, 1H), 8.10 (s, 1H), 8.02 (t, J=8 Hz, 1H), 7.86 (d, J=6Hz, 1H), 7.86 (s, 1H), 7.72 (d, J=8 Hz, 2H), 7.63 (d, J=9 Hz, 2H), 7.59(dd, J=8 Hz, J=5 Hz, 1H), 7.05 (br s, 1H), 4.85 (d, J 9 Hz, 1H), 4.42(d, J=15 Hz, 1H), 4.16 (dd, J=14 Hz, J=10 Hz, 1H), 4.06 (d, J=4 Hz, 1H),4.01 (br s, 1H), 4.00-3.86 (m, 1H), 1.64-1.44 (m, 1H), 1.42-1.36 (m,1H), 1.16-1.04 (m, 4H), 0.97 (s, 9H), 0.68 (t, J=7 Hz, 3H); HRMSC₂₉H₃₇F₃N₅O₅S m/z 624.2468 (M+H)_(cal); 624.2477 (M+H)_(Obs).

Example 12 Preparation of(1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 12a Preparation of 4-nitrophenyl(1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propylCarbonate

To 562.0 mg (1.80 mmol) of(2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanolin 18 mL of 1,2-dichloroethane at room temperature was added 544.1 mg(2.70 mmol) of 4-nitrophenyl chloroformate. Then, 291.1 μL (3.60 mmol)of pyridine was added, and the solution was heated at reflux for 16 h.Saturated aqueous sodium bicarbonate was added, and the resultingmixture was extracted with ethyl acetate. The extract was dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by silica gel column chromatography eluting with an ethylacetate:hexanes solution (3:7) to give 779.7 mg (91%) of 4-nitrophenyl(1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propylcarbonate. R_(f)=0.21 (3:7 ethyl acetate:hexanes); ¹H-NMR (300 MHz,DMSO-d₆): δ 8.29 (d, J=8 Hz, 2H), 7.87 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz,2H), 7.63 (s, 1H), 7.33 (d, J=9 Hz, 2H), 6.52 (s, 1H), 4.71 (d, J=9 Hz,1H), 4.64 (d, J=15 Hz, 1H), 4.33 (dd, J=15 Hz, J=10 Hz, 1H), 0.89 (s,9H); ES-LCMS m/z 478 (M+H).

Example 12b Preparation of(1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To 96.6 mg (268.2 μmol) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamidehydrochloride at room temperature was added 116.4 mg (243.8 μmol) of4-nitrophenyl(1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propylcarbonate in 4.9 mL of dimethylformamide. This was followed by theaddition of 169.9 μL (975.2 μmol) of N,N-diisopropylethylamine, and thereaction mixture was stirred for 19 h at room temperature. The solutionwas concentrated, saturated sodium bicarbonate was added, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with saturated sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby silica gel column chromatography eluting with an ethylacetate:hexanes solution (9:1) to give 93.2 mg (61%) of a mixture ofalcohols. The alcohols were dissolved in 3.0 mL of dichloromethane atroom temperature, 79.0 mg (186.2 μmol) of Dess-Martin periodinane wasadded, and the reaction mixture was stirred for 120 min. It was pouredinto saturated sodium metabisulfite, and the resulting mixture wasneutralized with saturated sodium bicarbonate and extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography eluting with an ethyl acetate:hexanes solution(7:3) to give 42.2 mg (45%) of(1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. R_(f)=0.24(7:3 ethyl acetate:hexanes); ¹H-NMR (300 MHz, DMSO-d₆, Temp=110° C.):δ8.61 (d, J=4 Hz, 1H), 8.02 (t, J=8 Hz, 1H), 7.86 (d, J=8 Hz, 1H), 7.81(d, J=8 Hz, 2H), 7.72 (d, J=9 Hz, 2H), 7.62 (br s, 1H), 7.61 (dd, J=8Hz, J=5 Hz, 1H), 7.43 (s, 1H), 7.03 (br s, 1H), 6.34 (s, 1H), 4.79 (d,J=9 Hz, 1H), 4.39 (d, J=14 Hz, 1H), 4.15 (dd, J=13 Hz, J=11 Hz, 1H),4.10-3.90 (ABX, 2H), 3.90-3.86 (m, 1H), 1.66-1.52 (m, 1H), 1.48-1.30 (m,1H), 1.28-1.08 (m, 4H), 0.83 (s, 9H), 0.81 (t, J=7 Hz, 3H); HRMSC₂₉H₃₇F₃N₅O₅S m/z 624.2468 (M+H)_(cal); 624.2474 (M+H)_(Obs).

Example 13 Preparation of(1S)-2,2-dimethyl-1-{[3-(3-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 13a Preparation of 3-(1H-pyrazol-3-yl)pyridine

A solution of 5.0 g (41.3 mmol) of 3-acetylpyridine and 5.4 g (45.4mmol) of dimethyl formamide dimethylacetal in 40 mL of anhydrousdimethylformamide was stirred at 130° C. for 4 h. Solvent wasevaporated, and the residue was triturated with diethyl ether to obtain5.7 g of a yellow solid. To a solution of the solid in 50 mL of methanolwas added 1.59 g (32 mmol) of hydrazine monohydrate. After 48 h at roomtemperature, solvent was removed and portions of acetonitrile weredistilled from the residue to provide 4.8 g (81%) of3-(1H-Pyrazol-3-yl)pyridine as a tan oil. ¹H-NMR (DMSO-d₆):δ 11.5 (br s,1H), 9.05 (d, J=2 Hz, 1H), 8.56 (dd, J=5 Hz, J=2 Hz, 1H), 8.10 (dt, J=8Hz, J=2 Hz, 1H), 7.65 (d, J=2 Hz, 1H), 7.33 (dd, J=8 Hz, J=5 Hz, 1H)6.66 (d, J=2 Hz, 1H); ES-LCMS m/z 2146 (M+H).

Example 13b Preparation of(2S)-3,3-dimethyl-1-[3-(3-pyridinyl)-1H-pyrazol-1-yl]-2-butanol

To a solution of 0.38 g (2.62 mmol) of 3-(1H-pyrazol-3-yl)pyridine and0.47 g (2.62 mmol) of (4S)-4-tert-butyl-1,3,2-dioxathiolane 2,2-dioxidein 15 mL of acetonitrile was added 1.3 g of a potassium fluoride/aluminamixture [prepared by mixing 10 g of potassium fluoride, 200 mL of water,and 15 g of activated neutral alumina (Brockmann I, 150 mesh) andconcentrating at 55° C.]. The mixture was stirred at ambient temperaturefor 4 h. Then, a solution of 2 mL of acetyl chloride in 10 mL ofmethanol was added to the reaction mixture. After 18 h, saturatedaqueous sodium bicarbonate was added, the mixture was filtered, and thefilter cake was rinsed with methanol. The filtrate was concentrated, andthe residue was partitioned between saturated aqueous sodium bicarbonateand dichloromethane. The organic phase was dried over sodium sulfate andconcentrated to provide 0.6 g (94%) of(2S)-3,3-dimethyl-1-[3-(3-pyridinyl)-1H-pyrazol-1-yl]-2-butanol as ayellow solid. ¹H-NMR (DMSO-d₆): δ 8.97 (s, 1H), 8.45 (d, J=4 Hz, 1H),8.1 (t, J=8 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.38 (dd, J=8 Hz, J=5 Hz,1H), 4.86 (d, J=6 Hz, 1H), 4.27 (dd, J=13 Hz, J=2 Hz, 1H), 3.90 (dd,J=14 Hz, J=10 Hz, 1H), 3.5-3.4 (m, 1H), 0.90 (s, 9H).

Example 13c Preparation of(1S)-2,2-Dimethyl-1-{[3-(3-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl4-nitrophenyl Carbonate

(2S)-3,3-Dimethyl-1-[3-(3-pyridinyl)-1H-pyrazol-1-yl]-2-butanol wastreated with p-nitrophenyl chloroformate as previously described inexample 1g to provide the title compound as a solid foam. ¹H-NMR(DMSO-d₆): δ 8.97 (s, 1H), 8.46 (d, J=4 Hz, 1H), 8.13 (d, J=9 Hz, 2H),8.10 (d, J=8 Hz, 1H), 7.9 (d, J=2 Hz, 1H), 7.38 (dd, J=7 Hz, J=4 Hz,1H), 7.22 (d, J=9 Hz, 2H), 6.83 (d, J=2 Hz, 1H), 4.90 (d, J=9 Hz, 1H),4.62 (d, J=14 Hz, 1H), 4.35 (dd, J=14 Hz, J=9 Hz, 1H), 1.03 (s, 9H).

Example 13d Preparation of(1S)-2,2-dimethyl-1-{[3-(3-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To 129.4 mg (359.1 μmol) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamidehydrochloride at room temperature was added 134.0 mg (326.5 μmol) of(1S)-2,2-dimethyl-1-{[3-(3-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl4-nitrophenyl carbonate in 6.5 mL of dimethylformamide. This wasfollowed by the addition of 227.5 μL (1.31 mmol) ofN,N-diisopropylethylamine, and the reaction mixture was stirred for 23 hat room temperature. It was concentrated, saturated sodium bicarbonatewas added, and the resulting mixture was extracted with ethyl acetate.The organic layer was washed with saturated sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by silica gel column chromatography eluting with methanol:ethylacetate (1:19) to give 138.8 mg (76%) of a mixture of alcohols. Thealcohols were dissolved in 4.9 mL of chloroform at room temperature,131.7 mg (310.5 μmol) of Dess-Martin periodinane was added, and thereaction mixture was stirred for 60 min. It was poured into saturatedsodium metabisulfite, and the resulting mixture was subsequentlyneutralized with saturated sodium bicarbonate before being extractedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by silicagel column chromatography eluting with ethyl acetate with 1% methanolsolution to give 91.6 mg (66%) of(1S)-2,2-dimethyl-1-{[3-(3-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. R_(f)=0.19(ethyl acetate); ¹H-NMR (300 MHz, DMSO-d₆, Temp=110° C.): δ 8.94 (s,1H), 8.62 (d, J=4 Hz, 1H), 8.46 (d, J=3 Hz, 1H), 8.06 (d, J=10 Hz, 1H),8.00 (d, J=8 Hz, 1H), 7.86 (d, J=8 Hz, 1H), 7.66 (d, J=2 Hz, 1H), 7.60(d, J=6 Hz, 1H), 7.58 (d, J=5 Hz, 1H), 7.36 (dd, J=8 Hz, J=5 Hz, 1H),7.05 (br s, 1H), 6.65 (d, J=2 Hz, 1H), 4.88 (d, J=9 Hz, 1H), 4.45 (dd,J=14 Hz, J=3 Hz, 1H), 4.19 (dd, J=14 Hz, J=10 Hz, 1H), 4.11 (d, J=6 Hz,1H), 4.05 (d, J=6 Hz, 1H), 4.00-3.86 (m, 1H), 1.66-1.48 (m, 1H),1.48-1.30 (m, 1H), 1.24-1.08 (m, 4H), 0.98 (s, 9H), 0.77 (t, J=6 Hz,3H); HRMS C₂₇H₃₇N₆O₅S m/z 557.2546 (M+H)_(Cal); 557.2561 (M+H)_(Obs).

Example 14 Preparation of(1S)-2,2-dimethyl-1-{[3-(4-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 14a Preparation of(1S)-2,2-dimethyl-1-{[3-(4-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl4-nitrophenyl Carbonate

4-Acetylpyridine was subjected sequentially to the procedures describedin examples 13a, 13b, & 13c to provide the title compound as a solidfoam. ¹H-NMR (DMSO-d₆): δ 8.53 (d, J=6 Hz, 2H), 8:14 (d, J=9 Hz, 2H),7.93 (d, J=2 Hz, 1H), 7.71 (d, J=6 Hz, 2H), 7.23 (d, J=9 Hz, 2H), 6.9(d, J=2 Hz, 1H), 4.89 (d, 10 Hz, 1H), 4.65 (br d, J=14 Hz, 1H), 4.37(dd, J=14 Hz, J=10 Hz, 1H), 1.04 (s, 9H).

Example 14b Preparation of(1S)-2,2-dimethyl-1-{[3-(4-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To 123.6 mg (343.1 μmol) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamidehydrochloride at room temperature was added 128.0 mg (311.9 μmol) of(1S)-2,2-dimethyl-1-{[3-(4-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl4-nitrophenyl carbonate in 6.2 mL of dimethylformamide. This wasfollowed by the addition of 217.3 μL (1.25 mmol) ofN,N-diisopropylethylamine, and the reaction mixture was stirred for 64 hat room temperature. It was concentrated, saturated sodium bicarbonatewas added, and the resulting mixture was extracted with ethyl acetate.The organic layer was washed with saturated sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by silica gel column chromatography eluting with methanol:ethylacetate (1:9) to give 159.1 mg (91%) of a mixture of alcohols. Thealcohols were dissolved in 5.7 mL of chloroform at room temperature,151.0 mg (355.0 μmol) of Dess-Martin periodinane was added, and thereaction mixture was stirred for 60 min. It was poured into saturatedsodium metabisulfite, and the resulting mixture subsequently neutralizedwith saturated sodium bicarbonate before being extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by silica gelcolumn chromatography eluting with methanol:ethyl acetate (1:19) to give53.4 mg (34%) of(1S)-2,2-dimethyl-1-{[3-(4-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. R_(f)=0.32(1:19 methanol:ethyl acetate); ¹H-NMR (300 MHz, DMSO-d₆, Temp=110° C.):δ 8.62 (d, J=5 Hz, 1H), 8.53 (d, J=5 Hz, 2H), 8.01 (t, J=8 Hz, 1H), 7.85(d, J=8 Hz, 1H), 7.69 (s, 1H), 7.68 (d, J=5 Hz, 2H), 7.60 (d, J=6 Hz,1H), 7.58 (d, J=6 Hz, 1H), 7.07 (br s, 1H), 6.73 (d, J=2 Hz, 1H), 4.87(d, J=9 Hz, 1H), 4.46 (dd, 3J=17 Hz, 1H), 4.20 (dd, J=15 Hz, J=10 Hz,1H), 4.12-3.94 (ABX, 2H), 3.92 (m, 1H), 1.66-1.50 (m, 1H), 1.50-1.30 (m,1H), 1.28-1.08 (m, 4H), 0.97 (s, 9H), 0.77 (t, J=7 Hz, 3H); HRMSC₂₇H₃₇N₆O₅S m/z 557.2546 (M+H)_(Cal); 557.2542 (M+H)_(Obs).

Example 15 Preparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 15a Preparation of(2S)-1-(5,6-dichloro-1H-benzimidazol-1-yl)-3,3-dimethyl-2-butanol

A solution of 2.08 g (11.1 mmol) of 5,6-dichloro-1H-benzimidazole and2.00 g (11.1 mmol) of (4S)-4-tert-butyl-1,3,2-dioxathiolane 2,2-dioxidein 28 mL of N,N-dimethylformamide was stirred as 1.57 g (11.4 mmol) ofpotassium carbonate was added. The mixture was stirred at 60° C. for 18h, and then cooled in an ice bath. A solution of 12 mL of acetylchloride in 120 mL of methanol was then added. The reaction mixture wasstirred for one day, and concentrated. The residue was partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic phase was concentrated, and the residue was slurried in ethylacetate. The solid was isolated by filtration to yield 1.88 g of(2S)-1-(5,6-dichloro-1H-benzimidazol-1-yl)-3,3-dimethyl-2-butanol. Thefiltrate was concentrated, and the residue was purified by silica gelcolumn chromatography eluting with ethyl acetate to yield an additional0.50 g (total yield 2.38 g, 74%) of the title compound. ¹H-NMR (300 MHz,DMSO-d₆): δ 8.29 (d, J=8 Hz, 2H), 7.90 (s, 1H), 7.86 (s, 1H), 4.96 (d,J=6 Hz, 1H), 4.39 (dd, J=14 Hz, J=2 Hz, 1H), 3.98 (dd, J=14 Hz, J=10 Hz,1H), 3.32 (m, overlapping H₂O), 0.95 (s, 9H).

Example 15b Preparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl4-nitrophenyl Carbonate

A solution of 2.38 g (8.29 mmol) of(2S)-1-(5,6-dichloro-1H-benzimidazol-1-yl)-3,3-dimethyl-2-butanol and1.36 mL (16.6 mmol) of pyridine in 83 mL of 1,2-dichloroethane wasstiffed as 3.34 g (16.6 mmol) of 4-nitrophenylchloroformate was added.The solution was stirred at 95° C. for one day, and then partitionedbetween ethyl acetate and saturated aqueous sodium bicarbonate. Theorganic phase was washed with brine, and concentrated. The residue waspurified by silica gel column chromatography eluting with ethyl acetateto yield 1.68 g (sample contains 0.33 EtOAc by ¹H-NMR for an effectiveweight of 1.58 g, 42%) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl4-nitrophenyl carbonate. ¹H-NMR (300 MHz, DMSO-d₆): δ 8.44 (s, 1H), 8.20(d, J=9 Hz, 2H), 8.01(s, 1H), 7.96 (s, 1H), 6.94 (d, J=9 Hz, 2H), 4.85(m, 1H), 4.74 (m, 1H), 4.57 (m, 1H), 1.09 (s, 9H); ES-LCMS m/z 452(M+H)⁺ retention time=4.33 min.

Example 15c Preparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate

73 mg (0.18 mmol) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamidehydrochloride was slurried in 3.5 mL of anhydrous dimethylformamide.Addition of 80 mg (0.18 mmol) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl4-nitrophenyl carbonate followed by 0.14 mL (0.72 mmol) ofdiisopropylethylamine resulted in a light yellow solution, which wasstirred for 3 d. It was then concentrated under reduced pressure. Theresulting residue was dissolved in ethyl acetate, and the solution waswashed with a saturated aqueous sodium bicarbonate solution., dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by silica gel chromatography eluting with a methanol:chloroformsolution (1:9) to afford 54 mg (50%) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate.ES-LCMS n/z 622 (M+Na) retention time=3.96 min.

Example 15d Preparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To a solution of 50.5 mg (0.084 mmol) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamatein 2.2 mL of chloroform was added 44.6 mg (0.105 mmol) of Dess-Martinperiodinane. The mixture was stirred at room temperature for 1.25 h, andthen diluted with ethyl acetate. A saturated aqueous sodium thiosulfatesolution was added, and the two layers were mixed vigorously before asaturated aqueous solution of sodium bicarbonate was added. The organicphase was dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography eluting with ahexane:acetone solution (1:1) to yield 19 mg (38%) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. ES-LCMS m/z598 (M+H)⁺ retention time=4.00 min. HRMS C₂₆H₃₃Cl₂NS₅O₅S m/z 598.1658(M+H)_(Cal); 598.1674 (M+H)_(Obs).

Example 16 Preparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

Example 16a Preparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate& (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To a solution of 386 mg (1.12 mmol) of tert-butyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate& tert-butyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamatein 3.3 mL of anhydrous dioxane was added 20 mL of a 4 N solution ofhydrogen chloride in dioxane, and the resulting solution was stirred for60 min, during which a white precipitate formed. The mixture wasconcentrated, leaving a white solid which was dried under vacuum, andthen slurried in 3 mL of anhydrous dimethylformamide. Addition of 0.44mL (2.24 mmol) of diisopropylethylamine resulted in a light yellowsolution, to which 200 mg (0.44 mmol) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl4-nitrophenyl carbonate was added. The resulting solution was stirredfor 1 d, and then concentrated. The residue was diluted with ethylacetate, and the resulting solution was washed with a saturated aqueoussodium bicarbonate solution. After drying over magnesium sulfate,volatiles were removed under vacuum, and the residue was purified bysilica gel chromatography eluting with a methanol:chloroform solution(1:9) to afford 0.14 g (57%) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate& (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate.ES-LCMS m/z 558 (M+H) retention time=3.52min.

Example 16b Preparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To a solution of 0.13 g (0.23 mmol) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate& (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamatein 6 mL of chloroform was added 42 mg (0.1 mmol) of Dess-Martinperiodinane, and the reaction mixture was stirred at room temperaturefor 1.25 h. The mixture was diluted with ethyl acetate and saturatedaqueous sodium thiosulfate solution. The layers were mixed vigorously,and then a saturated aqueous sodium bicarbonate solution was added. Thelayers were separated, and the organic extract was dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography eluting with a methanol:chloroform solution(1:9) to yield 64 mg (50%) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamateES-LCMS m/z 556 (M+H)⁺ retention time=3.66 min. HRMS C₂₃H₂₇Cl₂N₅O₅S m/z556.1188 (M+H)_(Cal); 556.1193 (M+H)_(Obs).

Example 17 Preparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate Example 17aPreparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(2S)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate &(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(2R)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To a solution of 370 mg (1.12 mmol) of tert-butyl(2S)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate &tert-butyl (2R)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamatein 3.3 mL of anhydrous dioxane, 20 mL of a 4 N solution of hydrogenchloride in dioxane was added. The resulting solution was stirred for 60min, during which time a white precipitate formed. The mixture wasconcentrated under reduced pressure and the resulting solid was driedunder vacuum. A 54 mg (0.1 8mmol) sample of the residue was then addedto a solution of 90 mg (0.2 mmol) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl4-nitrophenyl carbonate in 2 mL of dimethylformamide. Addition of 0.22mL (1.12 mmol) of diisopropylethylamine resulted in a light yellowsolution, which was stirred for 1 d under nitrogen, and thenconcentrated. The residue was then partition between ethyl acetate and asaturated aqueous sodium bicarbonate solution. The layers were separatedand the organic phase was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel chromatographyeluting with a methanol:chloroform solution (1:9) to afford 44 mg (45%)of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(2S)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate &(1s)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(2R)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate. ES-LCMSm/z 544 (M+H) retention time=3.60 min.

Example 17b Preparation of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate

To a solution of 43 mg (0.079 mmol) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(2S)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate &(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(2R)-2-hydroxy-3-[(2-pyridinylsulfonyl)amino]propylcarbamate in 2 mL ofchloroform was added 42 mg (0.1 mmol) of Dess-Martin periodinane, andthe mixture was stirred at room temperature for 1.25 h. An additionalportion of 21 mg (0.05 mmol) of Dess-Martin periodinane was added, andthe reaction mixture was stirred for another 0.5 h. The mixture wasdiluted with ethyl acetate and a saturated aqueous sodium thiosulfatesolution. The combined layers were mixed vigorously and then a saturatedaqueous sodium bicarbonate solution was added. The layers were separatedand the organic phase was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography eluting with a methanol:chloroform solution (1:9). Thesample was further purified by HPLC using a Waters Symmetry C18 19mm×150 mm column with 7 μm packing eluted with a five minute gradient of30% -70% acetonitrile in water. The mobile phase contained a 0.1%trifluoroacetic acid modifier. This purification yielded 4 mg (9%) of(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl2oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate. ES-LCMS m/z 542(M+H) retention time=3.59 min. HRMS C₂₂H₂₅Cl₂N₅O₅S m/z 542.1032(M+H)_(Cal); 542.1026 (M+H)_(Obs).

Example 18 Preparation of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

Example 18a Preparation of 4-[4-(trifluoromethyl)phenyl]-1H-imidazole

A mixture of 2.21 g (8.28 mmol) of 4-(trifluoromethyl)phenacylbromideand 9.3 mL (234 mmol) of formamide was stirred at 175° C. for 3 h. Then,30 mL of 1N hydrochloric acid was added to the resulting solution, whichwas then heated to reflux. The resulting mixture was filtered and thefiltrate was allowed to cool to room temperature before neutralizationwith concentrated ammonium hydroxide. The resulting mixture waspartitioned between ethyl acetate and brine. The organic phase was driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was partially purified by silica gel column chromatographyeluting with an ethyl acetate:methanol solution (9:1). Furtherpurification by silica gel chromatography eluting with a hexane:acetonesolution (1:1) yielded 1.18 g (67%) of4-[4-(trifluoromethyl)phenyl]-1H-imidazole. ¹H-NMR (DMSO-d₆): δ 12.34(br s, 1H), 7.96 (d, J=8 Hz, 2H), 7.77 (s, 1H), 7.76 (s, 1H), 7.68 (d,J=8 Hz, 2H).

Example 18b Preparation of(2S)-3,3-dimethyl-1-{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}-2-butanol

A solution 594 mg (5.94 mmol) of (S)-3,3-dimethyl-1,2-epoxybutane and1.26 g (5.94 mmol) of 4′-trifluoromethyl-4-phenyl imidazole in 2.5 mL ofethanol was placed in a sealed tube and heated at 85° C. for 4 d. Themixture was cooled and concentrated, and the residue was purified bysilica gel column chromatography eluting with ethyl acetate to yield1.56 g (84%) of(2S)-3,3-dimethyl-1-{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}-2-butanol.¹H-NMR (DMSO-d₆): δ 7.93 (d, J=8 Hz, 2H), 7.84 (s, 1H), 7.68 (m, 3H),5.01 (d, J=6 Hz, 1H), 4.15 (d, J=14 Hz, 1H), 3.73 (m, 1H), 3.31 (m,overlapping H₂O), 0.91 (s, 9H).

Example 18c Preparation of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl4-nitrophenyl Carbonate

To solution of 1.91 g (6.12 mmol) of(2S)-3,3-dimethyl-1-{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}-2-butanolin 82 mL of tetrahydrofuran at 0° C. was added 4.2 mL (6.7 mmol) of 1.6M n-butyllithium in hexanes, and the resulting solution was stirred for10 min. A solution of 1.85 g (9.19 mmol) of 4-nitrophenyl chloroformatein 38 mL of tetrahydrofuran was added, and the solution was stirred atroom temperature for 19 h. Saturated aqueous sodium bicarbonate was thenadded, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby silica gel chromatography eluting with an ethyl acetate:hexanessolution (6:4) to give 1.83 g (sample contains 0.5 ethyl acetate by¹H-NMR for an effective weight of 1.68 g, 57%) of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl4-nitrophenyl carbonate. ¹H-NMR (DMSO-d₆): δ 8.12 (d, J=7 Hz, 2H), 7.94(d, J=8 Hz, 2H), 7.93 (s, 1H), 7.86 (s, 1H), 7.70 (d, J=8 Hz, 2H). 7.23(d, J=9 Hz, 2H), 4.86 (d, J=8 Hz, 1H),4.51 (d, J=13 Hz, 1H),4.24(dd,J=14 Hz, J=10 Hz, 1H), 1.05(s, 9H).

Example 18d Preparation of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate

First, 0.24 mL (1.2 mmol) of diisopropylethylamine was added to amixture of 179 mg (0.36 mmol) of(3S)-3-amino-2-hydroxy-N-(3-pyridinylmethyl)heptanamide dihydrochloridein 3 mL of anhydrous dimethylformamide. Then, 0.15 g (0.3 mmol) of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl4-nitrophenyl carbonate was added. The resulting solution was stirredfor 3 d. It was then concentrated under reduced pressure, and theresulting residue was diluted with ethyl acetate. The resulting solutionwas washed with a saturated aqueous sodium bicarbonate solution, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by silica gel chromatography eluting with amethanol:chloroform solution (1:9) to afford 0.20 g (sample contains0.67 chloroform and 0.25 dimethylformamide by ¹H-NMR for an effectiveweight of 0.173 g, 92%) of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate&(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate.ES-LCMS m/z 626 (M+H) retention time=3.45 min.

Example 18e Preparation of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To a solution of 0.20 g (0.28 mmol) of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamateand(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamatein 3 mL chloroform was added 0.15 g (0.35 mmol) Dess-Martin periodinane.The reaction mixture was stirred at room temperature for 1.5 h, thendiluted with ethyl acetate and a saturated aqueous sodium thiosulfatesolution. The layers were mixed vigorously, and then a saturated aqueoussodium bicarbonate solution was added. The layers were separated, andthe organic phase was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography eluting with a methanol:chloroform solution (1:9) toyield 83.2 mg (48%) of(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. ES-LCMS m/z624 (M+H) retention time=3.51 min. HRMS C₂₉H₃₆F₃N₅O₅S m/z 624.2468(M+H)_(Cal); 624.2463 (M+H)_(Obs).

Example 19 Preparation of(1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate Example 19aPreparation of(1S)-1-{[4-(1H-Imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl4-nitrophenyl Carbonate

4-(Imidazol-1-yl)phenol was subjected to the procedure described inexample 15a, and then treated with p-nitrophenyl chloroformate asdescribed in example 15b to afford the title compound as a solid foam.1H-NMR (DMSO-d₆: δ 8.31 (d, J=9 Hz, 2H), 8.14 (s, 1H), 7.65 (s, 1H),7.55 (d, J=9 Hz, 2H), 7.51 (d, J=9 Hz, 2H), 7.11 (d, J=9 Hz, 2H), 7.06(s, 1H), 4.93 (dd, J=9 Hz, J=2 Hz, 1H), 4.43 (dd, J=11 Hz, J=2 Hz, 1H),4.16 (dd, J=11 Hz, J=9 Hz, 1H), 1.04 (s, 9H).

Example 19b Preparation of(1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate

To 154 mg (0.31 mmol) ofN-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride& N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide in 3 mL ofdimethylformamide, 132 mg (0.31 mmol) of(1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl4-nitrophenyl carbonate was added, followed by 0.25 mL (1.43 mmol) ofN,N-diisopropylethylamine. The reaction mixture was stirred for 18 h atroom temperature. It was concentrated, a saturated sodium bicarbonatesolution was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with a saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by silica gel columnchromatography eluting with an methanol:chloroform solution (1:9) toyield 101.3 mg (57%) of(1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamateand (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate.ES-LCMS m/z 574 (M+H) Rt=2.7 min.

Example 19c Preparation of(1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate

To a solution of 96.6 mg (0.17 mmol) of(1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate& (1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamatein 1.7 mL of chloroform was added 85 mg (0.2 mmol) of Dess-Martinperiodinane, and the mixture was stirred at room temperature for 1 h. Asecond portion of 15 mg (0.035 mmol) of Dess-Martin periodinane wasadded, and the reaction mixture was stirred for 0.5 h. It was thendiluted with ethyl acetate and a saturated aqueous sodium thiosulfatesolution. The layers were mixed vigorously, before a saturated aqueoussodium bicarbonate solution was added. The layers were separated, andthe organic phase was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography eluting with a methanol:chloroform solution (1:9) toyield 21.6 mg (23%) of(1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. ES-LCMS m/z572 (M+H) retention time=2.83 min. HRMS C₂₈H₃₇N₅O₆S m/z 572.2543(M+H)_(Cal); 572.2526 (M+H)_(Obs).

Biological Data

The compounds of the present invention elicit important and measurablepharmacological responses. Each of the compounds exemplified in theExamples section bind with high affinity (IC₅₀<10 μM) to the cathepsin Kenzyme, as described by the cathepsin K assay recited below.

All assays for cathepsin K were carried out with human and ratrecombinant enzyme. Assays for cathepsins S & V were also carried outwith human recombinant enzyme. Assays for human cathepsins B, H, and Lwere carried out with enzyme prepared from human liver tissue. Standardassay conditions for the determination of kinetic constants used afluorogenic peptide substrate, typically(5S,8S)-13-amino-5-benzyl-13-imino-3-methylene-N-(4-methyl-2-oxo-2H-chromen-7-yl)-6-oxo-1-phenyl-2-oxa-4,7,12-triazatridecane-8-carboxamide(Cbz-Phe-Arg-AMC), and were determined in 100 mM sodium acetate at pH5.5 containing 10 mM dithiothreitol and 120 mM sodium chloride. A stocksubstrate solution of Cbz-Phe-Arg-AMC was prepared at a concentration of50 mM in dimethyl sulfoxide. This substrate was diluted into the assayfor a final substrate concentration of 10 μM in the rat cathepsin K,human cathepsin K, and human cathepsin B assays; a final substrateconcentration of 5 μM in the human cathepsin L assay; and a finalsubstrate concentration of 2 μM in the human cathepsin V assay.

A stock substrate solution of benzyl(1S)-1-{[((1S)-1-{[((1S)-4-{[amino(imino)methyl]amino}-1-{[(4-methyl-2-oxo-2H-chromen-7-yl)amino]carbonyl}butyl)amino]carbonyl}-2-methylpropyl)amino]carbonyl}-2-methylpropylcarbamate(Cbz-Val-Val-Arg-AMC) was prepared at a concentration of 10 mM indimethyl sulfoxide. This substrate was diluted into the assay for afinal substrate concentration of 10 μM in the human cathepsin S assay.

A stock substrate solution of(2S)-2-amino-5-{[amino(imino)methyl]amino}-N-(2-naphthyl)pentanamidehydrochloride (L-Arg-_(β)-naphthalamide HCl) was prepared at aconcentration of 10 mM in dimethyl sulfoxide. This substrate was dilutedinto the assay for a final substrate concentration of 50 μM in thecathepsin H assay.

All assays contained 10% dimethyl sulfoxide. Independent experimentsfound that this level of dimethyl sulfoxide had no effect on enzymekinetic constants. All assays were conducted at 30° C. Productfluorescence (excitation at 360 nm; emission at 440 nm, (exceptcathepsin H which used excitation at 340 nm; emission at 420 nm)) wasmonitored with a PerSeptive Biosystems Cytofluor II fluorescence platereader. Product progress curves were generated over 2.3 h monitoring theformation of 7-amino-4-methylcoumarin product (or _(β)-naphthalamide forcathepsin H).

Human and Rat Cathepsin K:

Scale-Up and Fermentation: The method of O'Reilly et al. (1994) was usedfor baculovirus expression with the following details: Two liters ofSpodoptera frugiperda (Sf-9) cells (ATCC) were grown in Grace'sSupplemented medium (Life Technologies) supplemented with 2 g/L glucose,10% fetal bovine serum (HyClone) and 0.1% pluronic F-68 (LifeTechnologies). Cells were grown in a 6 L shake flask at 150 RPM at 28°C. for 24 h to a density of 106 cells/mL, and then infected at amultiplicity of infection (MOI) of 0.1. The cells continued to grow for72 h post-infection, before the virus was harvested by centrifugation at1400×g for 30 min. Virus was titered as described (Summers and Smith,1987).

One and one-half liters of Trichoplusia ni (T. ni) High Five (TM) cells[JRH Biosciences, Woodland, Calif. (adapted to suspension and serum-freemedium)] grown in Excell 405 (TM) medium (JRH Biosciences) with 50 ug/mLgentamicin (Life Technologies) were added to a 15 L stirred tank reactor(Quark Enterprises, Inc) at a density of ˜0.5×106 cells/mL. The cellswere grown for 24 h at 28° C., 50 RPM, and 50% dissolved oxygen. Cellswere then infected at a density of ˜106 cells/mL with an MOI of 1 andgrown for 48 h post-infection. Media were separated from cells at a rateof 1 L/min using the Centritech 100 (TM) continuous-flow centrifuge(DuPont) operating at 200×g.

Protein Purification: Media (human and rat) were filtered through aWhatman 3 filter, and then loaded onto a 25 mL Poros HS II (26 mm×47 mm)cation exchange column equilibrated in 25 mM sodium acetate at pH 5.5(equilibration buffer). The column was washed until the absorbancereached the baseline value, and then the protein was eluted with alinear gradient from 0-2 M sodium chloride in the equilibration buffer.Column fractions were analyzed by SDS-PAGE, N-terminal sequencing, andmass spectrometry. Fractions containing the proform of cathepsin K werepooled and frozen at −80° C. The proform was concentrated in an AmiconCentriprep 10 and fractionated with a Superdex 75 column (26 mm×600 mm,Pharmacia) equilibrated in 400 mM sodium chloride, 25 mM sodium acetateat pH 5.5.

Cathepsin K Activation: The proform of cathepsin K was converted tomature cathepsin K by brief exposure to pH 4 in the presence of 5 mML-cysteine. Typically, 5 mM L-cysteine was added to 10 mL ofapproximately 1 mg/mL procathepsin K. One mL of this solution wasdiluted ten-fold into 450 mM sodium acetate at pH 4.0 containing 5 mML-cysteine. This solution was reacted at 23° C. for 2 min beforeneutralization with 2 mL 1.8 M sodium acetate at pH 6.0. The neutralizedsample was added to the remaining 9 mL of procathepsin K. The mixturewas incubated at 4° C. for 2-3 days. The activated cathepsin K waschromatographed on a Poros HS II column as described above.

Inhibition Studies

Potential inhibitors were evaluated using the progress curve method.Assays were carried out in the presence of variable concentrations oftest compound. Reactions were initiated by addition of bufferedsolutions of inhibitor and substrate to enzyme. Data analysis wasconducted according to one of two procedures depending on the appearanceof the progress curves in the presence of inhibitors. For thosecompounds whose progress curves were linear, the enzymatic activity(RATE) was plotted against the concentration of test compound, includinginhibitor concentration of zero ([I]=0), and the IC₅₀ determined from afit of equation 1 to the data,RATE=V _(max)/(1+([I]/IC50))  (1)where V_(max) is the best fit estimate of the maximal enzymaticactivity. K_(i) values were calculated from IC₅₀ values using equation 2assuming a competitive model. $\begin{matrix}{K_{i} = {{IC}_{50}*\left\lbrack {1 - \frac{S}{\left( {S + K_{m}} \right)}} \right\rbrack}} & (2)\end{matrix}$

For those compounds whose progress curves showed downward curvaturecharacteristic of time-dependent inhibition, the data from individualsets was analyzed using the computer program DynaFit (Kuzmic, P. Anal.Biochem. ₁₉₉₆, 237, 260-273) to give K_(i) values according to thefollowing kinetic mechanism:E+S⇄ESES→E+PE→EXE+I⇄EI

TABLE 1 Inhibition of Cathepsin K (K_(i) in nM) Example hCat K IC₅₀ 1+++ 2 +++ 3 +++ 4 + 5 ++++ 6 ++ 7 +++ 8 ++ 9 +++ 10 ++ 11 +++ 12 +++ 13++++ 14 ++++ 15 ++++ 16 ++++ 17 ++++ 18 ++++ 19 +++++ Inhibitors (about 10,000-1,000 nM)++ Potent inhibitors (about 1000 to 100 nM)+++ More potent inhibitors (about 100 to 10 nM)++++ Most potent inhibitors (about 10-1 nM, or less)

TABLE 2 Inhibition of Cathepsins (Ki in nM) hCat B hCat K hCat L hCat ShCat V Example IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ 6 + ++ + +++ ++ 16 +++ ++++ +++++++ +++++ Inhibitors (about 10,000-1,000 nM)++ Potent inhibitors (about 1000 to 100 nM)+++ More potent inhibitors (about 100 to 10 nM)++++ Most potent inhibitors (about 10-1 nM, or less)

Although specific embodiments of the present invention have beenillustrated and described in detail, the invention is not limitedthereto. The above detailed description of preferred embodiments isprovided for example only and should not be construed as constitutingany limitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included within the scope ofthe appended claims.

1. A compound of Formula (I):

or a salt, solvate, or physiological functional derivatives thereof,wherein A is the group defined by (Q³)_(p)-(Q²)_(n)-(Q¹)-(Q)_(m)-,wherein Q is CH₂ and m is 0, 1, or 2, or Q is OCH₂ and m is 1, or Q isN(R³)CH₂ and m is 1, where R³ is hydrogen or C₁-C₆ alkyl; Q¹ is aryl,heteroaryl, or heterocyclyl; Q² is CH₂ and n is 0 or 1, or Q² is 0 and nis 1, or Q² is N(R³) and n is 1, where R³ is hydrogen or C₁-C₆ alkyl; Q³is aryl or heteroaryl and p is 0 or 1; R¹ is alkyl or cycloalkyl, saidcycloalkyl may be optionally substituted with alkyl; D is O or S; R² ishydrogen or alkyl; and Z is —(X¹)_(q)—(X²); wherein X¹ is S(O)₂, C(O),or —CH₂—, and q is 0, 1, or 2; and X² is aryl, heteroaryl, orheterocyclyl.
 2. The compound of claim 1 wherein Q is CH₂ and m is
 1. 3.The compound of claim 1 wherein Q¹ is heteroaryl.
 4. The compound ofclaim 1 wherein n is 0;
 5. The compound of claim 1 wherein Q³ is aryl,said aryl being substituted with haloalkyl and p is
 1. 6. The compoundof claim 1 wherein Q¹ is


7. The compound of claim 1 wherein Q³ is


8. The compound of claim 1 wherein A is


9. The compound of claim 1 wherein R¹ is lower alkyl.
 10. The compoundof claim 1 wherein R¹ is t-butyl.
 11. The compound of claim 1 wherein R¹is


12. The compound of claim 1 wherein R² is hydrogen, methyl, or n-butyl.13. The compound of claim 1 wherein R² is methyl or n-butyl.
 14. Thecompound of claim 1 wherein R² is n-butyl.
 15. The compound of claim 1wherein R² is


16. The compound of claim 1 wherein Z is —(X¹)_(q)—(X²) wherein X¹ isS(O)₂; q is 1; and X² is heteroaryl.
 17. The compound of claim 1 whereinZ is


18. The compound of claim 1 wherein Z is


19. The compound of claim 1 wherein Z is


20. The compound as claimed in claim 1, selected from the groupconsisting of:(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(4-morpholinylcarbonyl)amino]acetyl}pentylcarbamate;(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(6-fluoro-2-pyridinyl)amino]acetyl}pentylcarbamate;(3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-2,2-dimethyl-1-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]propyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-2,2-dimethyl-1-{[3-(3-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-2,2-dimethyl-1-{[3-(4-pyridinyl)-1H-pyrazol-1-yl]methyl}propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl(1S)-1-methyl-2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;(1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl2-oxo-3-[(2-pyridinylsulfonyl)amino]propylcarbamate;(1S)-2,2-dimethyl-1-({4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}methyl)propyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate;(1S)-1-{[4-(1H-imidazol-1-yl)phenoxy]methyl}-2,2-dimethylpropyl(1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate.
 21. Acompound of Formula (II):

or a salt, solvate, or pharmaceutically functional derivative thereof,wherein B is -(Q¹)_(a)-(Q² )_(b)-(Q³) wherein Q¹ is C(O), S(O)₂, orCR²R³, where R² and R³ each are independently selected from hydrogen orC₁-C₆ alkyl, and a is 0, 1, 2, or 3; Q² is O, S, NR², or CR²R³, where R²and R³ each are independently selected from hydrogen or C₁-C₆ alkyl, andb is 0, 1, 2, or 3; and Q³ is aryl, heteroaryl, heterocyclyl, aralkyl,or alkylene-heterocyclyl; R¹ is hydrogen or alkyl; Z is —(X¹)_(q)—(X²);wherein X¹ is S(O)₂, C(O), or alkyl, and q is 0 or 1; and X² is aryl,heteroaryl, or heterocyclyl.
 22. The compound of claim 21 wherein a is0; b is 0; and Q³ is heterocyclyl.
 23. The compound of claim 21 whereinQ³ is:


24. The compound of claim 21 wherein Z is —(X¹)_(p)—(X²) where X¹ isS(O)₂; p is 1; and X² is heteroaryl.
 25. The compound of claim 21wherein Z is


26. A pharmaceutical composition comprising: a therapeutically effectiveamount of a compound as claimed in claim 1
 27. A pharmaceuticalcomposition comprising: a therapeutically effective amount of a compoundas claimed in claim 1, or a salt, solvate, or a physiologicallyfunctional derivative thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients.
 28. A method of treating adisorder in a mammal, said disorder being characterized by enhanced boneturnover which can ultimately lead to fracture, comprising:administering to said mammal a therapeutically effective amount of acompound as claimed in claim 1 or a salt, solvate or a physiologicallyfunctional derivative thereof.
 29. A method of treating a disorder in amammal, said disorder being characterized by bone loss, comprising:administering to said mammal a therapeutically effective amount of acompound as claimed in claim 1 or a salt, solvate or a physiologicallyfunctional derivative thereof.
 30. (Cancel)
 31. (Cancel)
 32. A method oftreating osteoporosis, comprising: administering to said mammal atherapeutically effective amount of a compound as claimed in claim 1, ora salt, solvate or physiologically functional derivative thereof.
 33. Amethod of treating osteoporosis, comprising: administering to saidmammal therapeutically effective amounts of (i) a compound as claimed inclaim 1, or a salt, solvate or physiologically functional derivativethereof; and (ii) at least one bone building agent.
 34. A pharmaceuticalcomposition comprising: a therapeutically effective amount of a compoundas claimed in claim
 21. 35. A pharmaceutical composition comprising: atherapeutically effective amount of a compound as claimed in claim 21,or a salt, solvate, or a physiologically functional derivative thereofand one or more of pharmaceutically acceptable carriers, diluents andexcipients.
 36. A method of treating a disorder in a mammal, saiddisorder being characterized by enhanced bone turnover which canultimately lead to fracture, comprising: administering to said mammal atherapeutically effective amount of a compound as claimed in claim 21 ora salt, solvate or a physiologically functional derivative thereof. 37.A method of treating a disorder in a mammal, said disorder beingcharacterized by bone loss, comprising: administering to said mammal atherapeutically effective amount of a compound as claimed in claim 21 ora salt, solvate or a physiologically functional derivative thereof. 38.A method of treating osteoporosis, comprising: administering to saidmammal a therapeutically effective amount of a compound as claimed inclaim 21, or a salt, solvate or physiologically functional derivativethereof.
 39. A method of treating osteoporosis, comprising:administering to said mammal therapeutically effective amounts of (i) acompound as claimed in claim 21, or a salt, solvate or physiologicallyfunctional derivative thereof; and (ii) at least one bone buildingagent.